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Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.

TitleTrans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.
Publication TypeJournal Article
Year of Publication2016
AuthorsLiu C-T, Raghavan S, Maruthur N, et al.
Secondary AuthorsMeigs JB
Corporate AuthorsAAAG Consortium, CARe Consortium, COGENT-BP Consortium, eMERGE Consortium, MEDIA Consortium, MAGIC Consortium
JournalAm J Hum Genet
Volume99
Issue1
Pagination56-75
Date Published2016 Jul 07
ISSN1537-6605
KeywordsAfrican Continental Ancestry Group, Asian Continental Ancestry Group, Blood Glucose, Continental Population Groups, Diabetes Mellitus, Type 2, Enhancer Elements, Genetic, Ethnic Groups, European Continental Ancestry Group, Fasting, Female, Gene Frequency, Genome-Wide Association Study, Humans, Insulin, Insulin Resistance, Introns, Islets of Langerhans, Male, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcription Factors
Abstract

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

DOI10.1016/j.ajhg.2016.05.006
Alternate JournalAm J Hum Genet
PubMed ID27321945
PubMed Central IDPMC5005440
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