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Human whole-exome genotype data for Alzheimer's disease.

ABSTRACT: The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community.

SUBMITTER: Leung YY

PROVIDER: S-EPMC10805795 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Human whole-exome genotype data for Alzheimer's disease.

Leung Yuk Yee YY Naj Adam C AC Chou Yi-Fan YF Valladares Otto O Schmidt Michael M Hamilton-Nelson Kara K Wheeler Nicholas N Lin Honghuang H Gangadharan Prabhakaran P Qu Liming L Clark Kaylyn K Kuzma Amanda B AB Lee Wan-Ping WP Cantwell Laura L Nicaretta Heather H Haines Jonathan J Farrer Lindsay L Seshadri Sudha S Brkanac Zoran Z Cruchaga Carlos C Pericak-Vance Margaret M Mayeux Richard P RP Bush William S WS Destefano Anita A Martin Eden E Schellenberg Gerard D GD Wang Li-San LS

Nature communications 20240123 1

The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically ...[more]

PMID: 38263370

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Project description:ImportancePrevious genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles.ObjectiveTo identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing.Design, setting, and participantsThe discovery stage included 10 441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018.Main outcomes and measuresScore, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ε4 carriers and noncarriers. Results with P ≤ 1 × 10-5 were further evaluated in the replication data sets and combined by meta-analysis.ResultsAmong 3145 patients with AD and 4213 controls lacking ε4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0; P = 2.22 × 10-7) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10-8). GPAA1 was also associated with expression in the brain of GPAA1 (β = -0.08; P = .03) and its repressive transcription factor, FOXG1 (β = 0.13; P = .003), and global cognition function (β = -0.53; P = .009). Significant gene-wide associations (threshold P ≤ 6.35 × 10-7) were observed for OR8G5 (P = 4.67 × 10-7), IGHV3-7 (P = 9.75 × 10-16), and SLC24A3 (P = 2.67 × 10-12) in 2377 patients with AD and 706 controls with ε4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women).Conclusions and relevanceThe study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ε4 alleles that reinforce known and suggest additional pathways leading to AD.

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Human whole-exome genotype data for Alzheimer's disease.

Publications

Human whole-exome genotype data for Alzheimer's disease.

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