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Abstract

Objective

Synonymous variants can lead to disease; nevertheless, the majority of sequencing studies conducted in Alzheimer disease (AD) only assessed coding variation.

Methods

To detect synonymous variants modulating AD risk, we conducted a whole-genome sequencing study on 67 Caribbean Hispanic (CH) families multiply affected by AD. Identified disease-associated variants were further assessed in an independent cohort of CHs, expression quantitative trait locus (eQTL) data, brain autopsy data, and functional experiments.

Results

Rare synonymous variants in 4 genes (CDH23, SLC9A3R1, RHBDD2, and ITIH2) segregated with AD status in multiplex families and had a significantly higher frequency in these families compared with reference populations of similar ancestry. In comparison to subjects without dementia, expression of CDH23 (β = 0.53, p = 0.006) and SLC9A3R1 (β = 0.50, p = 0.02) was increased, and expression of RHBDD2 (β = −0.70, p = 0.02) decreased in individuals with AD at death. In line with this finding, increased expression of CDH23 (β = 0.26 ± 0.08, p = 4.9E-4) and decreased expression of RHBDD2 (β = −0.60 ± 0.12, p = 5.5E-7) were related to brain amyloid load (p = 0.0025). SLC9A3R1 expression was associated with burden of TDP43 pathology (β = 0.58 ± 0.17, p = 5.9E-4). Using eQTL data, the CDH23 variant was in linkage disequilibrium with variants modulating CDH23 expression levels (top single nucleotide polymorphism: rs11000035, p = 4.85E-6, D' = 1.0). Using minigene splicing assays, the CDH23 and SLC9A3R1 variants affected splicing efficiency.

Conclusions

These findings suggest that CDH23, SLC9A3R1, RHBDD2, and possibly ITIH2, which are involved in synaptic function, the glutamatergic system, and innate immunity, contribute to AD etiology. In addition, this study supports the notion that synonymous variants contribute to AD risk and that comprehensive scrutinization of this type of genetic variation is warranted and critical.
Alzheimer disease (AD), the most frequent cause of dementia, is a major public health burden, affecting currently 5.1 million persons in the United States and posing a projected burden of over 13.8 million affected individuals by the year 2050.1 Genome-wide association studies (GWASs) conducted over the past 15 years have identified over 25 common variants with low effect sizes (odds ratios ranging from 1.1 to 1.25) at over 25 loci containing genes predominantly clustering in inflammation/immune response, lipid metabolism, and endocytosis/trafficking pathways.2 Recent studies using next-generation sequencing technologies identified in addition rare risk or protective variants in a set of genes, with odds ratios more similar to that of 1 APOEε4 allele, which also largely cluster in these pathways.36
Following the traditional dogma of molecular biology postulating that only nonsynonymous mutations, i.e., variants that alter the encoded amino acid, have an effect on the protein sequence, and thereby cellular function, most of the sequencing studies conducted have only assessed coding variants resulting in amino acid substitutions, usually identified via an ensemble of commonly applied annotations and scores predicting effects based on amino acid substitutions and conservation. However, although previously called silent mutations, it is now recognized that synonymous variants can have deleterious effects and cause disease by altering splicing, translation, messenger RNA structure, protein folding, protein expression, and enzymatic activity.7 Identification of these disease-associated synonymous variants is not only critical to explain the missing heritability of disease but can also significantly advance the understanding of the underlying molecular disease etiology and help identify preventive and therapeutic targets.
To identify rare, synonymous variants associated with AD, we used whole-genome sequencing on 67 Caribbean Hispanic (CH) families highly loaded for AD. The frequency of AD in these families is approximately 5 times more than in non-Hispanic white individuals of similar age, significantly increasing statistical power for rare variant identification.8 Putative disease-associated variants were validated in an independent data set of CH subjects, expression quantitative trait locus (eQTL) and brain autopsy data from the ROS/MAP study, and functional analyses determining the effect of select identified variants on splicing.

Methods

Samples selected for whole-genome sequencing

The 67 families included in the whole genome sequencing (WGS) are part of the Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohort that has been described elsewhere in detail.9 EFIGA study participants were recruited since January 1998 from the Alzheimer Disease Research Center Memory Disorders Clinic at Columbia University in New York City and hospitals in the Dominican Republic and Puerto Rico. Diagnosis of individuals with AD was validated by standardized neurologic and neuropsychological evaluations. Assessment of family history was conducted to determine existence of additional living relatives with AD; if existence of affected siblings was confirmed, all other living relatives were assessed via standardized medical, neurologic, and neuropsychological examinations. All study participants were followed up in 18-month intervals completing at each visit a standardized assessment of medical history, physical and neurologic examination, and an extensive neuropsychological battery10 assessing cognitive function in key domains affected by aging and dementia, including memory, visuospatial function, executive function, and psychomotor speed, applying the Selective Reminding Test, the Benton Visual Retention Test, the Rosen Drawing Test, the Boston Naming Test, the Controlled Oral Word Association Test, the Category Fluency Test, the Color Trails Test, the Similarities subtest from the Wechsler Adult Intelligence Scale, and the orientation items from the Mini-Mental State Examination. Functional status was evaluated using the Disability and Functional Limitation Instrument. Severity of cognitive impairment was assessed using The Clinical Dementia Rating Scale. Diagnosis of AD was made based on National Institute of Neurological and Communicative Disorders and Stroke–the Alzheimer Disease and Related Disorders Association guidelines in a consensus conference consisting of physicians and neuropsychologists. APOE genotypes were derived by a modification of the protocol described by Hixson and Vernier.11 To optimize ability to identify novel sequence variants in the WGS analyses, priority was given to families most heavily affected by AD (≥4 affected members with DNA available) and lowest frequency of the APOEε4 allele. On average, 5 individuals per family underwent WGS.

Preparation of samples for whole-genome sequencing

The Qiagen Gentra Puregene salting out method was used for isolation of high-molecular-weight genomic DNA from blood. Genomic DNA from saliva was isolated using prepIT.L2P (DNA Genotek Inc., Ottawa, Canada). DNA concentrations were determined by fluorescence base determination (pico green).
Whole-genome sequence data in the 67 families (302 affecteds and 49 unaffecteds) were generated at Baylor University, the Broad Institute, and Washington University (i.e., 3 National Human Genome Research Institute Large Scale Sequencing and Analysis Centers). Using the Burrows-Wheeler Aligner (v0.6.2), sequence reads were aligned to the GRCh37 reference genome, and variant calling was performed using the Atlas V2 and Genome Analysis Tool Kit–HaplotypeCaller pipelines. Discrepancies between calls from both pipelines were reconciled creating a consensus data set. Variants not labeled “Pass” or with a low mapping score (QUAL score <22, Prob <0.95), low read depth (<6), an out of range variant read to total read depth (<3 reads or <10% alternate read for heterozygotes), or variants in regions represented by a single strand (>0.99) were removed, similar to monomorphic variants, variants with high missingness (>20%), variants with excessive heterozygosity (|z| > 1.22 for minor allele frequency [MAF] <0.2, |z |> 5 SD for MAF≥0.2), and variants with very high read depth (>500 reads). Annotation of variants passing quality control was based on ANNOVAR and included functional prediction by SIFT, PolyPhen2, and GERP. Allele frequencies were derived from the Exome Sequencing Project, 1000 Genomes, and the Exome Aggregation Consortium (ExAC).

Postmortem brain data from the ROS/MAP cohort

All postmortem brain data were generated as part of the Religious Orders Study12 and Rush Memory and Aging Project13 (ROS/MAP): 2 ongoing, longitudinal cohort studies of aging coordinated out of the Rush Alzheimer's Disease Center (RADC) in Chicago, IL. All subjects are older and recruited free of dementia (mean age at entry 78 ± 9 years), are administered annual cognitive and clinical assessments, and sign an Anatomical Gift Act.

RNA sequencing and gene expression quantification

Gene expression data were generated using RNA-seq from the dorsolateral prefrontal cortex (DLPFC) of 638 ROS/MAP subjects, according to previously published methods.14 Briefly, RNA was extracted using the Qiagen miRNeasy mini kit and RNase-Free DNase Set. Libraries were prepared by the Broad Institute's Genomic Platform (strand-specific 2'-deoxyuridine 5'-triphosphate method and poly-A selection). Sequencing was performed using the Illumina HiSeq platform (50 million paired-end reads, 101bp each). Alignment was performed using Trinity to the GENCODE v14 transcriptome (GRCh37; gencodegenes.org/releases/). Quantification of gene counts was performed using RNA-Seq by Expectation Maximization, batch normalization with Combat, and mean-variance correction weights calculated using the edgeR and voom Bioconductor packages in R (v3.4.1).

Postmortem neuropathologic assessment

All ROS/MAP subjects were administered detailed neuropathologic evaluations at autopsy by a board-certified neuropathologist who was blinded to clinical data. Five Alzheimer disease–related pathologies were evaluated: neuritic and diffuse plaque counts, neurofibrillary tangle counts, immunohistochemical quantifications of total β-amyloid by image analysis (continuous), and TDP43 proteinopathy (4 ordinal stages).15 Detailed descriptions of each pathologic measure are readily available at the RADC website (radc.rush.edu/).

Standard protocol approvals, registrations, and patient consents

The EFIGA study was approved by the Institutional Review Board of Columbia University. All participants or their guardians provided written informed consent. All study protocols of the ROS/MAP cohort were approved by the Institutional Review Board of Rush University Medical Center, and all study participants have provided informed, written consent and signed a repository consent that allows their data to be shared.

Data availability

Anonymized data for the WGS data set can be obtained by qualified investigators through the database of Genotypes and Phenotypes (phs000572.v1.p1) and through the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (niagads.org). Data generated from ROS/MAP can be obtained via the RADC Resource Sharing Hub (radc.rush.edu/).

Statistical methods

Single-marker association and gene-based tests for variant validation

Variants that were found to segregate with AD status in the sequenced families and were therefore included in the follow-up genotyping in all family members and the 444 unrelated controls were checked for Hardy-Weinberg equilibrium and tested for association with AD using a generalized linear mixed model accounting for population structure and relatedness. Models were first adjusted for kinship coefficient, age, and sex and subsequently in addition for APOE genotype. For a second, independent validation, we leveraged GWAS data available in an independent set CHs of individuals from the Washington Inwood Columbia Aging Project16 and conducted gene-based tests using Sequence Kernel Association Test optimal test adjusting for principal components for population substructure, age, sex, and subsequently in addition for APOE genotype.
To assess whether the variants associated with AD were enriched in these families, we used data from the Genome Aggregation Database (gnomAD) (gnomad.broadinstitute.org/), which includes 123,136 whole exomes and 15,496 whole genomes from unrelated individuals from various ethnic groups that were derived by a variety of large-scale disease-specific and population genetic sequencing projects. To determine enrichment of putative disease-associated synonymous variants in the family set, we compared their allele frequencies with the gnomAD Latino population using a Fisher exact test first including all family members and then selecting only 1 affected from each family.

Expression quantitative trait locus analyses

Expression QTL analyses were performed in DLPFC tissue from 494 ROS/MAP subjects for 13,484 expressed genes (average sequencing depth = 90 million reads). Genotype data for this analysis were imputed using BEAGLE (v.3.3.2) and the 1000 Genomes Project Consortium interim phase 1 haplotype reference data set. Details of the methodology and results of eQTL analyses have been recently published,17 and full summary statistics have been made publicly available for query and download (mostafavilab.stat.ubc.ca/xqtl/).
Statistical correction for multiple testing of the marginal cis-eQTL results was reassessed for this study according to the estimated number of effective tests, which was calculated using the Genetic Type I Error Calculator18 and takes into account linkage disequilibrium in each region of interest. Using this method, p values were first corrected within each selected locus (including a buffer of 100 kb around each target gene) and then underwent Bonferroni correction for the number of independent loci tested (n = 4). For example, at CDH23, this yielded a significance threshold of p < 2.9 × 10-5 (0.05/437.55 effective tests/4 loci).

Association of gene expression with clinical diagnosis and neuropathologic endophenotypes of AD in the ROS/MAP cohort

To detect associations between the expression of target genes and clinical diagnosis at death or levels of postmortem neuropathology, gene counts from voom were analyzed in robust linear models using iterative reweighted least squares regression (implemented in the MASS R package), covarying for effects of sex, age at death (age at last visit for clinical AD diagnosis), postmortem interval, RNA integrity, APOEε4 status, first 3 genomic principal components calculated using EIGENSTRAT, and composition of cell types. Significance was based on a conservative Bonferroni threshold of p < 0.0025 (0.05/4 genes/5 tested pathologies).

Analysis of effect of identified variants on splicing

Minigene constructs

Reference and variant allele sequences were obtained by gene synthesis from GenScript (Piscataway Township, NJ). Subsequent cloning of the synthetized sequences (table 5) was performed following methods previously described.19 PUC19 plasmid vector and Gateway cloning vectors pENTR/D-TOPO (Invitrogen) and pDESTsplice minigene splicing vectors (Addgene; ref#32484) were used to obtain the final minigene splicing vectors. Final constructs for CDH23 were verified by restriction digestion with BstEII and HindIII, and final constructs for SLCA3R1 were verified by restriction digestion with SbfI and HindII followed by DNA sequencing (Genewiz, South Plainfield, NJ).
Table 1 Characteristics of the discovery sample set

In vitro transfection

HEK 293 cells (2.5 × 105) were transfected with 0.75 μg of plasmid DNA carrying either the reference allele or variant allele of interest using CalFectinTM Mammalian DNA Transfection Reagent (SignaGen Laboratories, Ijamsville, MD). We performed 3 transfection replicates for each plasmid. After 24 hours, RNA isolation from the 3 replicates was performed using the RNeasy® Plus mini kit (Qiagen). The First Strand complementary DNA (cDNA) Synthesis Kit (Origene, Rockville, MD) was used to generate cDNA from 500 ng of the RNA following the manufacturer's instructions.

Analysis of minigene expression

The cDNA containing the spliced products of the minigene vector was amplified using the Phusion High-Fidelity DNA Polymerase (New England Biolabs) using previously reported PCR primers specific for the rat insulin 2 exons (5′-CCTGCTCATCCTCTGGGAGC-3′ and 5′-AGGTCTGAAGGTCACGGGCC-3′).19 PCR conditions were set at 98°C denaturation for 30 seconds, followed by 35 cycles of 98°C for 7 seconds, 62°C for 30 seconds, and 72°C for 1 minute, with a final 72°C hold for 5 minutes. Products were visualized by gel electrophoresis, and subsequent DNA gel extraction/sequencing was performed to confirm that the spliced sequences were flanked by rat insulin 2 exon sequences and were mapped to the CDH23/SC9A3R1 genomic sequence using BLAT. Following previously described methods,19 quantitation of the cDNA products was performed in parallel using the same forward PCR primer, with an additional tag at the 5′ end with 6-FAMTM to enable measurement of differences in the size and quantity of the reference and variant minigene products. Quantitation samples were run on the Applied Biosystems (ABI) ABI 3730xl DNA Analyzer (Genewiz, South Plainfield, NJ). The ABI internal lane size standard GeneScan 500 LIZ was run with all the samples, which allows to accurately sizing 35–500 bp fragments. Quantitation data were analyzed using GeneMapperTM and Peak ScannerTM (ThermoFisher Scientific) software. In addition, PCR products of the cDNA were sequenced (Genewiz, DNA Sanger sequencing) to determine the precise boundaries generated during splicing. The sequences were verified by confirming that the spliced sequences were flanked by rat insulin 2 exon sequences following previously validated methods19 and were mapped to the CDH23 and SLCA3R1 genomic sequences using BLAT.

Results

Analysis of sequencing data

Characteristics of the discovery data sets are shown in table 1. Variant calling, recalibration, and application of quality control filters resulted in 97,866 synonymous variants, out of which 46,897 were rare. Eleven variants (located in RHBDD2, ITIH2, ANK3, CDH23, OTUD7A, EDC4, FUK, SLC9A3R1, MBP, CC2D1A, and TGM6) segregated with late-onset Alzheimer disease (LOAD) status in the whole exome sequencing or WGS data set and were genotyped for validation in all family members of the discovery families, 48 additional multiplex CH families (total 115 families with 1,024 subjects genotyped), and 444 independent controls of similar age and ancestry. Genotyping for all variants was successful in all these subjects. In linear mixed models adjusted for kinship, age, sex, and APOE genotype, the variants located in SLC9A3R1 (rs41282067), ITIH2 (rs143731868), and RHBDD2 (rs190871206) remained significantly associated with LOAD (p ≤ 0.005 adjusted for multiple testing, table 2), and the variant in CDH23 (rs56013867) was close to significance. Twenty-two of the 539 affected individuals in the 115 genotyped families carried the SLC9A3R1 variant, 16 carried the RHBDD2 variant, 10 the ITIH2 variant, and 20 the CDH23 variant. For all variants, these frequencies were significantly higher than the expected frequencies based on the gnomAD database (gnomad.broadinstitute.org/; Fisher exact test p value <0.0001). When restricting the analyses to 1 affected person per family, and using the overall number of alleles genotyped or sequenced for each variants as denominator in the Fisher exact test, the results remained significant for all 4 variants (RHBDD2 (p < 0.0001), ITIH2 (p < 0.0001), CDH23 (0.0004), and SLC9A3R1 (p < 0.0001)). In gene-based tests including synonymous and functional variants or synonymous variants only in these genes in an independent cohort of 1,511 subjects of the same ancestry (779 affecteds and 732 unaffecteds), CDH23, SLC9A3R1, and ITIH2 were replicated (ITIH2: p = 0.03, CDH23: p = 0.04, and SLC9A3R1: p = 0.03). All 4 genes have a positive constraint metric for synonymous variants based on ExAC data suggesting intolerance to variation (exac.broadinstitute.org/) and are expressed in the brain.
Table 2 General linear model relating candidate variants with AD diagnosis in 115 families and 444 independent controls
Table 3 Association between gene expression and clinical diagnosis of AD in the ROS/MAP data set

Association between gene expression, clinical diagnosis, and pathologic AD phenotypes in the ROS/MAP cohort

To further validate the association of these 4 genes with AD, we explored the association of their expression with clinical Alzheimer dementia diagnosis proximate to death and AD brain pathology in the ROS/MAP cohort (n = 400). Compared with individuals without cognitive impairment, expression of CDH23 (β = 0.53, p = 0.006) and SLC9A3R1 (β = 0.50, p = 0.02) was increased, and expression of RHBDD2 (β = −0.70, p = 0.02) decreased in persons with a clinical diagnosis of AD (table 3). In line with this finding, higher expression of CDH23 (beta = 0.26 ± 0.08, p = 4.9E-4) and lower expression of RHBDD2 (beta = −0.60 ± 0.12, p = 5.5E-7) were related to brain β-amyloid load (Bonferroni-corrected p value for multiple testing = 0.0025; table 4). SLC9A3R1 expression was associated with burden of TDP43 pathology (beta = 0.58 ± 0.17, p = 5.9E-4). Using the eQTL data available in the ROS/MAP data set, the identified CDH23 variant—while not present itself on the microarray chip—was shown to be in linkage disequilibrium with a set of single nucleotide polymorphisms modulating CDH23 expression levels (top single nucleotide polymorphism: rs11000035 at 73625754bp, p = 4.85E-6, D' = 1.0).
Table 4 Association between gene expression and AD pathologic outcomes in the ROS/MAP data set
Table 5 Summary information for the variants tested by the minigene splicing assay

Analysis of effect of identified variants on splicing

For accurate intron excision, splicing requires sequence components from both the intron and the exon. Synonymous variants can influence splicing accuracy or efficiency. To determine whether identified synonymous variants affect AD risk through an effect on splicing accuracy or efficiency, we performed minigene splicing assays. Although functional analysis by minigene assay resulted in unchanged splicing patterns between reference and variant alleles for rs56013867 (CDH23) and rs41282067 (SLC9A3R1), there was evidence of altered splicing efficiency for these variants (table 5; figure, A). Although the rs56013867 variant in CDH23 exon 50 showed a significant decrease, the rs41282067 variant in SLC9A3R1 exon 3 showed a significant increase in splicing efficiency compared with their reference sequences (figure, A). Fluorescent quantitation also showed lower splicing efficiency for the rs56013867 variant (CDH23) compared with the reference allele (relative fluorescence units 4,295 and 13,374, respectively) (figure, B) and a significantly higher splicing efficiency rate for the rs41282067 variant (SLC9A3R1) compared with the reference allele (relative fluorescence units 25,825 and 21,778, respectively) (figure, C).
Figure Experimental analysis of splicing interference by AD-associated synonymous variants
(A) Gel electrophoresis with splicing products collected following transient transfection into HEK 293 cells. Constructs with the reference and variant alleles were analyzed separately. White dotted rectangles indicate the bands of spliced products for CDH23 and SLC9A3R1; numbers correspond to band sizes. Results of quantitation with fluorescent labeled PCR primers (conducted in a separate experiment) are shown for variants rs56013867 (CDH23) (B) and rs41282067 (SLC9A3R1) (C), revealing different splicing efficiencies between reference and variant alleles. **p ≤ 0.01; ****p ≤ 0.0001 by 2-tailed Student t test.

Discussion

Capitalizing on this data set of heavily loaded CH families, we identified rare synonymous variants in 4 genes not previously implicated in AD by genome-wide association or sequencing studies (CDH23, SLC9A3R1, RHBDD2, and ITIH2) and demonstrated by functional splicing assays20 an effect of 2 of these variants on splicing efficiency.
All 4 genes identified are acting in pathways established in AD. There is strong evidence from previous epigenomic and functional studies for a role of CDH23 in AD. CDH23 encodes a member of the cadherin superfamily a group of calcium-dependent cell adhesion glycoproteins essential for cell-cell adhesion, morphogenesis, neuronal connectivity, and tissue integrity, highly expressed in the brain. In addition to a recent large-scale gene-gene interaction study on AD, which identified CDH23 as a risk gene,21 2 independent epigenome-wide association studies of AD identified overlapping methylation signals in CDH2322,23 and suggested that expression of CDH23 is increased in astrocytes near neuritic plaques,24 in line with our finding of an association of CDH23 with brain amyloid pathology. Astrocytes have a vital function in the brain circuitry and are critical for a variety of functions such as formation and maturation of synapses, modulation of synaptic activity and plasticity, neurotransmitter clearance, and homeostasis.25 Reactive astrocytes are induced by injury and disease and activated by neuroinflammatory microglia; both activated microglia and astrocytes are prominent features in AD.25
Further consistent with our findings of an association of CDH23 with amyloid pathology, epithelial cadherin (encoded by CDH1) binds to presenilin-1,26 and neural (N-) cadherin has been implicated in amyloid-β release via interaction with presenilin-1. In addition, N-cadherin plays an essential role in synapse function, and inhibition of N-cadherin function accelerates amyloid-β–induced synapse impairment.27
The SLC9A3R1 gene (solute carrier family 9 [sodium/hydrogen exchanger], isoform 3 regulatory factor 1) encodes a scaffold protein (Na+/H+ exchanger regulatory factor 1 [NHERF1]) that connects plasma membrane proteins to the actin cytoskeleton, thereby regulating their surface expression. Notably, NHERF1 modulates the cell surface expression of the glutamate transporter GLAST.28 A series of key pathologic changes of AD including deposition of Aβ in plaques, soluble Aβ oligomers, hyperphosphorylated tau protein, oxidative stress, and neuronal inflammation have been linked to increased activation of the glutamatergic system.2932 Notably, NHERF1 encoded by SLC9A3R1 also binds to β-catenin and stabilizes the interaction with E-cadherin at cell-cell junctions,33 indicating that our observations on the SLC9A3R1 and CDH23 genes might converge on a common mechanism.
The rhomboid domain containing 2 (RHBDD2) gene, also named RHBDL7, encodes a member of the highly conserved rhomboid family of membrane-bound proteases. Rhomboids bind membrane proteins and direct them with high precision into various different cellular pathways.34 As a result of this vital function, members of the rhomboid family have been implicated in a variety of diseases including AD and Parkinson disease. Rhomboid protease RHBDL4 (alias: RHBDD1), cleaves amyloid precursor protein inside the cell, causing it to bypass amyloidogenic processing, leading to reduced Aβ levels.35 In line with this notion, in our analyses, higher expression of RHBDD2 was associated with lower brain amyloid load. In addition, RHBDD2—similar to its homologs RHBDD1 and RHBDD3—has also been associated with stress response and apoptosis.3638
Although ITIH2 could not be validated by gene expression analyses in this study, it should not be readily discarded as a potential candidate gene. Inter-alpha inhibitor proteins (IAIPs) including ITIH2 are anti-inflammatory molecules, and recent studies in rodents have demonstrated that IAIPs play a critical role in regulating inflammatory response and cell survival in the CNS after brain injury.39,40 Over the past 10 years, large-scale genomic studies have firmly established immune response as an etiologic pathway in AD. Administration of human plasma–derived IAIPs following neonatal HI brain injury in rodents decreases neuronal cell death and improves cognitive and behavioral function.41
There is limited overlap of our results with the findings of the previous large GWAS. In part, this is likely due to our focus on rare variants (MAF< 0.05), which have not been well covered by most GWASs, our focus on CHs, which have been significantly underrepresented in previous genomic studies, and our focus on synonymous variants, which have been widely neglected by the first-pass analyses conducted in previous large-scale sequencing studies in AD.
A significant strength of this study lies in the ascertainment scheme. Prioritization of multigeneral families highly loaded for AD allows to detect disease-associated variants by segregation with disease status. Prioritization of families with minimal clustering for APOEε4 further enriches the analytic data set for disease-associated variants other than APOEε4, yielding an additional increase in power to detect novel variants. The focus on a minority population allows to detect novel loci not identified in studies of non-Hispanic whites. Related to the latter notion, a limitation of the study is the lack of an additional independent data set of CH families available for replication. However, validation of the identified loci in the larger set of families and independent controls, demonstration of a significantly higher frequency of the identified variants in our data set compared with reference populations, validation of identified variants in brain expression and eQTL data with both clinical and neuropathologic key outcomes of AD, and demonstration of an effect of the CDH23 and SLC9A3R1 mutant variants on splicing efficiency significantly reduce the likelihood of false-positive findings.
In summary, this study identified 4 rare synonymous variants in CDH23, SLC9A3R1, RHBDD2, and ITIH2 that modulate risk of AD in CH families and are associated with LOAD pathology. Although replication efforts in subjects of other ancestral background are critical to generalize these findings, and studies are needed to characterize in detail the impact of the identified variants in different cell types in the brain in vitro and in vivo, these genes cluster with amyloid precursor protein processing, synaptic function and plasticity, glutamatergic neurotransmitter signaling, and immune system/inflammation in pathways involved in AD etiology. In addition, this study strongly suggests that synonymous variants contribute to AD risk and that comprehensive scrutinization of this type of variant in AD research is warranted and critical. A comprehensive functional follow-up of the identified variants is needed to fully understand the exact mechanisms through which they exert their effect on AD.

Glossary

ABI
Applied Biosystems
AD
Alzheimer disease
CH
Caribbean Hispanic
DLPFC
dorsolateral prefrontal cortex
EFIGA
Estudio Familiar de Influencia Genetica en Alzheimer
ExAC
Exome Aggregation Consortium
GWAS
genome-wide association study
IAIP
inter-alpha inhibitor protein
MAF
minor allele frequency
NHERF1
Na+/H+ exchanger regulatory factor 1
RADC
Rush Alzheimer's Disease Center

Appendix Authors

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Information & Authors

Information

Published In

Neurology® Genetics
Volume 6Number 4August 2020

Publication History

Received: November 22, 2019
Accepted: May 5, 2020
Published online: June 8, 2020
Published in print: August 2020

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Disclosure

None of the authors have a conflict of interest. Go to Neurology.org/NG for full disclosures.

Study Funding

Data collection for the EFIGA Study was supported by the National Institute on Aging (NIA) and by the NIH (RF1AG015473). Data collection and sharing for Whicap was supported by the Washington Heights-Inwood Columbia Aging Project (WHICAP, RF1AG054023) funded by the National Institute on Aging (NIA). Dr. Reitz was further supported by NIH grants RF1AG054080, R01AG064614, U01AG052410, and P50AG008702. Dr. Santa-Maria was supported by NIH grants P50AG008702 and R01NS095922. The Religious Orders Study and Rush Memory and Aging Project are supported by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG36836, and U01AG61366. The whole-genome sequencing was conducted as part of the Alzheimer's Disease Sequencing Project (ADSP). The ADSP is comprised of 2 Alzheimer disease (AD) genetics consortia and 3 National Human Genome Research Institute (NHGRI)-funded Large Scale Sequencing and Analysis Centers (LSAC). The 2 AD genetics consortia are the Alzheimer's Disease Genetics Consortium (ADGC) funded by NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other NIH institutes and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs. Lindsay Farrer, Jonathan Haines, Richard Mayeux, Margaret Pericak-Vance, and Gerard Schellenberg); U01AG049505 to Dr. Sudha Seshadri; U01AG049506 to Dr. Eric Boerwinkle; U01AG049507 to Dr. Ellen Wijsman; and U01AG049508 to Dr. Alison Goate, and the Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate, U01AG052410 to Dr. Pericak-Vance, and U01 AG052409 to Drs. Seshadri and Fornage. Data generation and harmonization in the Follow-up Phases is supported by U54AG052427 to Drs. Schellenberg and Li-San Wang.

Authors

Affiliations & Disclosures

Min Tang, PhD
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Maria Eugenia Alaniz, PhD
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Daniel Felsky, PhD
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
Canadian Institutes of Health Research, Fellowship 2016-2019
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Koerner Family Foundation, Koerner New Scientist 2019-2024
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Badri Vardarajan, PhD
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
BISC Global: Bioinformatics consulting for industry projects Kodikaz: Bioinformatics consulting for genomics data in oncology
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Dolly Reyes-Dumeyer, BA
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Rafael Lantigua, MD
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Martin Medrano, MD
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
David A. Bennett, MD
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
(1) Vigorous Minds, Scientific Advisory Board (2) AbbVie - Data Monitoring Committee (3) EABs: India Institute of Science; MCSA; Columbia ADRC; CCNA; CIMA-Q, WFU, Emory, MODEL-AD, REGARDS (4) DMCs: HRS, MIDUS (5) National Advisory Council on Aging (6) Consultant, Origent Data Sciences NIH SBIR grant
Gifts:
1.
$100,000 Potamkin Prize from the American Brain Foundation April 2018
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
(1) Neurology, Editorial Board; (2) Current Alzheimer Research, Editorial Board; (3) Neuroepidemiology, Editorial Board (4) Journal of the Prevention of Alzheimer's Disease, Editorial Board (5) Journal of Alzheimer's Disease, Editorial Board (6) Alzheimer’s & Dementia: Translational Research & Clinical Interventions, Editorial Board
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Biogen - funding for analyses of our own data Neurovision - amyloid eye imaging
Research Support, Government Entities:
1.
NIH: P30AG10161, PI; R01AG15819, PI; R01AG17917, PI; R01AG36042, MPI; R01AG54058, PI; U01AG61356, MPI; R01AG52476, MPI,
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Philip L. de Jager, MD, PhD
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
1. Roche, member of advisory board2. Biogen, member of advisory board3. Puretech, member of advisory board
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Biogen IDEC: speaker honoraria Insitro: speaker honoraria
Editorial Boards:
1.
Journal of Neuroimmunology - member of the Editorial BoardNeuroepigenetics - associate editorMultiple Sclerosis journal - member of the Editorial Board
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Investigator-initiated research grants from- Biogen - Roche
Research Support, Government Entities:
1.
U01 AG046152 (DE JAGER/BENNETT) 09/20/13 ? 08/31/20Pathway discovery, validation and compound identification for Alzheimer?s disease The overall goal of the study is the discovery and preclinical validation of novel targets associated with molecular processes that lead to cognitive decline, the primary outcome of most AD trials.R01 AG048015 (DE JAGER)09/30/13 ? 04/30/20 Identifying, validating and targeting AD susceptibility networks in monocytesThe study involves implementing a novel strategy to characterize the functional consequences of genetic variants associated with Alzheimer?s disease susceptibility.RF1 AG057473 (DE JAGER/BENNETT)09/15/17 ? 08/31/20Deconstructing and modeling the single cell architecture of the Alzheimer brainR01 AG053960 (SHULMAN)09/01/16 ? 05/31/21 Tau-Sliceosome Interactions in Alzheimer?s DiseaseThis project implements a cross-species strategy including targeted proteomics in human clinicopathologic cohorts and genetic experiments in Drosophila models to investigate the novel hypothesis that disruption in the spliceosome and resulting splicing failure mediate Tau-induced neurodegeneration.RF1 AG036042 (BENNETT)08/01/16 ? 06/30/21 Exploring the Role of the Brain Epigenome: Cognitive Decline and Life ExperienceThe goal of the grant is to establish the extent of inter-individual variation in the transcriptome of the aging brain and to assess how it mediates the effect of risk factors related to cognitive decline and dementia.R01 Al130547 (ELYAMAN) 04/01/17 ? 03/31/22 Altered CD4+ T cell function in relation to the AHl1 MS locusThe principal goas of the proposed project are (1) to identify, in CD4+ T cells, the component genes of networks perturbed by the MS susceptibility loci (2) to understand their functional consequences on T cell behavior and (3) to determine if non-genetic risk factors interact with genetic susceptibility networks.U01 AG061356 (DE JAGER) 09/30/18 ? 08/31/23Multi-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targetsThe primary goal of this study is to identify and disseminate a novel list of targets for AD treatment by characterizing validated genes in greater detail, integrate new AMP-AD data sets from groups involved, and perturb prioritized genes to identify critical domains within selected candidates.U01AG058589 (DESTEFANO)09/30/19 ? 08/31/23Therapeutic target discovery in ADSP data via comprehensive whole-genome analysis incorporating ethnicdiversity and systems approachesR01AG058683 (WIDOM)01/01/19 ? 12/31/23Child Maltreatment and Risk for Mild Cognitive Impairment and Alzheimer's DiseaseP50AG008702 (SMALL)02/01/2019 ? 5/31/2020Determining the subsets and role(s) of aging human microglia in Alzheimer?s diseaseThe general objective of the ADRC at Columbia University is to tackle the main barriers in the field of Alzheimer?s disease and related disorders, which include early detection, prevention and intervention.
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
National MS SocietyPI, 2008: JF2138A1CS-0000000289 (DE JAGER)09/01/19 ? 08/31/23Creating and deploying a toolkit for human microglia in neurodegenerationRoche IN003259 (DE JAGER)10/01/17 ? 09/30/21Creation of a reference map of single cell transcriptomes of clinically and neuropathologically well characterized aging human frontal cortex and white matterUnderstanding neurodegenerative disease mechanisms by investigating single cell transcriptomes of clinicallyand neuropathologically well characterized normal aging human frontal cortex and white matter.PDF Center Grant (PRZEDBORSKI)07/01/19 ? 06/30/20Differential neuronal susceptibility as an avenue toward disease-modifying therapy for Parkinson?s DiseaseOur long-term goal is to establish an integrated approach that leverages this differential neuronal susceptibility to capture a multidimensional signature associated with PD neurodegeneration and to use this knowledge for subsequent development of biomarkers and neuroprotective strategies for PD and related conditions.
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Richard Mayeux, MD, MSc
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Consultant to the Alzheimer's Disease Center at Rush University Medical School
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
RF1AG054023 Genetic Epidemiology of Cerebrovascular Factors in Alzheimer's Disease
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Ismael Santa-Maria, PhD
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Christiane Reitz, MD, PhD
From the The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science, Departments of Pharmacology and Neurology, University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
(1) National Institute of Health (NIH) grant RF1AG054080, MPI (2) National Institute of Health (NIH) grant R01AG064614, MPI (3) National Institute of Health (NIH) grant U01AG052410, MPI (4) National Institute of Health (NIH) grant P50AG008702, Core Leader
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence Dr. Reitz [email protected]
Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the NIH.

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