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Meta-analysis of Alzheimer's disease on 9,751 samples from Norway and IGAP study identifies four risk loci.

ABSTRACT: A large fraction of genetic risk factors for Alzheimer's Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from Norway and 25,580 cases and 48,466 controls from the International Genomics of Alzheimer's Project (IGAP), denoted the discovery sample. Second, we selected the top hits (p?

SUBMITTER: Witoelar A

PROVIDER: S-EPMC6308232 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Meta-analysis of Alzheimer's disease on 9,751 samples from Norway and IGAP study identifies four risk loci.

Witoelar Aree A Rongve Arvid A Almdahl Ina S IS Ulstein Ingun D ID Engvig Andreas A White Linda R LR Selbæk Geir G Stordal Eystein E Andersen Fred F Brækhus Anne A Saltvedt Ingvild I Engedal Knut K Hughes Timothy T Bergh Sverre S Bråthen Geir G Bogdanovic Nenad N Bettella Francesco F Wang Yunpeng Y Athanasiu Lavinia L Bahrami Shahram S Le Hellard Stephanie S Giddaluru Sudheer S Dale Anders M AM Sando Sigrid B SB Steinberg Stacy S Stefansson Hreinn H Snaedal Jon J Desikan Rahul S RS Stefansson Kari K Aarsland Dag D Djurovic Srdjan S Fladby Tormod T Andreassen Ole A OA

Scientific reports 20181227 1

A large fraction of genetic risk factors for Alzheimer's Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from ...[more]

PMID: 30591712

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Project description:More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10-8) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10-8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10-2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10-2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10-3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.

Dataset Information

Meta-analysis of Alzheimer's disease on 9,751 samples from Norway and IGAP study identifies four risk loci.

Publications

Meta-analysis of Alzheimer's disease on 9,751 samples from Norway and IGAP study identifies four risk loci.

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