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Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

ABSTRACT: INTRODUCTION:Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. METHODS:We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. RESULTS:Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10-8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ?4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10-6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10-6). DISCUSSION:Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

SUBMITTER: Jun GR

PROVIDER: S-EPMC5496797 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

Jun Gyungah R GR Chung Jaeyoon J Mez Jesse J Barber Robert R Beecham Gary W GW Bennett David A DA Buxbaum Joseph D JD Byrd Goldie S GS Carrasquillo Minerva M MM Crane Paul K PK Cruchaga Carlos C De Jager Philip P Ertekin-Taner Nilufer N Evans Denis D Fallin M Danielle MD Foroud Tatiana M TM Friedland Robert P RP Goate Alison M AM Graff-Radford Neill R NR Hendrie Hugh H Hall Kathleen S KS Hamilton-Nelson Kara L KL Inzelberg Rivka R Kamboh M Ilyas MI Kauwe John S K JSK Kukull Walter A WA Kunkle Brian W BW Kuwano Ryozo R Larson Eric B EB Logue Mark W MW Manly Jennifer J JJ Martin Eden R ER Montine Thomas J TJ Mukherjee Shubhabrata S Naj Adam A Reiman Eric M EM Reitz Christiane C Sherva Richard R St George-Hyslop Peter H PH Thornton Timothy T Younkin Steven G SG Vardarajan Badri N BN Wang Li-San LS Wendlund Jens R JR Winslow Ashley R AR Haines Jonathan J Mayeux Richard R Pericak-Vance Margaret A MA Schellenberg Gerard G Lunetta Kathryn L KL Farrer Lindsay A LA

Alzheimer's & dementia : the journal of the Alzheimer's Association 20170207 7

<h4>Introduction</h4>Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.<h4>Methods</h4>We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loc ...[more]

PMID: 28183528

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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.

Project description:Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10(-5) were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P?=?9.18×10(-8), OR?=?0.69, 95% CI [0.60-0.79]; rs6457617, P?=?1.14×10(-7) and rs9275245, P?=?1.39×10(-7). Within the MHC region, the next most associated SNP (rs3130573, P?=?1.86×10(-5), OR?=?1.36 [1.18-1.56]) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10(-5)) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P?=?5.70×10(-10), OR:1.25), TNIP1 (P?=?4.68×10(-9), OR:1.31), and RHOB loci (P?=?3.17×10(-6), OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis.

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Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

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Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

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