Dataset Information

Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans.

ABSTRACT: INTRODUCTION:African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS:We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS:Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION:An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.

SUBMITTER: Mez J

PROVIDER: S-EPMC5318231 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans.

Mez Jesse J Chung Jaeyoon J Jun Gyungah G Kriegel Joshua J Bourlas Alexandra P AP Sherva Richard R Logue Mark W MW Barnes Lisa L LL Bennett David A DA Buxbaum Joseph D JD Byrd Goldie S GS Crane Paul K PK Ertekin-Taner Nilüfer N Evans Denis D Fallin M Daniele MD Foroud Tatiana T Goate Alison A Graff-Radford Neill R NR Hall Kathleen S KS Kamboh M Ilyas MI Kukull Walter A WA Larson Eric B EB Manly Jennifer J JJ Haines Jonathan L JL Mayeux Richard R Pericak-Vance Margaret A MA Schellenberg Gerard D GD Lunetta Kathryn L KL Farrer Lindsay A LA

Alzheimer's & dementia : the journal of the Alzheimer's Association 20161020 2

<h4>Introduction</h4>African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power.<h4>Methods</h4>We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, ...[more]

PMID: 27770636

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Project description:Background & aimsThe inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities.MethodsWe performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance.ResultsWe detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles.ConclusionsWe performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Dataset Information

Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans.

Publications

Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans.

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