Title | Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Liu C-T, Raghavan S, Maruthur N, et al. |
Secondary Authors | Meigs JB |
Corporate Authors | AAAG Consortium, CARe Consortium, COGENT-BP Consortium, eMERGE Consortium, MEDIA Consortium, MAGIC Consortium |
Journal | Am J Hum Genet |
Volume | 99 |
Issue | 1 |
Pagination | 56-75 |
Date Published | 2016 Jul 07 |
ISSN | 1537-6605 |
Keywords | African 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. |
DOI | 10.1016/j.ajhg.2016.05.006 |
Alternate Journal | Am J Hum Genet |
PubMed ID | 27321945 |
PubMed Central ID | PMC5005440 |
Grant List | R01 HL059684-01A1 / HL / NHLBI NIH HHS / United States N01 HC095163 / HC / NHLBI NIH HHS / United States N01 HC095159 / HC / NHLBI NIH HHS / United States R01 DK078616 / DK / NIDDK NIH HHS / United States HHSN268201100012C / HL / NHLBI NIH HHS / United States U01 HL054472 / HL / NHLBI NIH HHS / United States R01 HL071025 / HL / NHLBI NIH HHS / United States N01 HC085086 / HC / NHLBI NIH HHS / United States U01 HL054471 / HL / NHLBI NIH HHS / United States R01 HL103612 / HL / NHLBI NIH HHS / United States HHSN268201300026C / HL / NHLBI NIH HHS / United States R01 HG003054 / HG / NHGRI NIH HHS / United States U01 HG004446 / HG / NHGRI NIH HHS / United States R01 HL087698 / HL / NHLBI NIH HHS / United States R01 HL046380 / HL / NHLBI NIH HHS / United States R00 DK081350 / DK / NIDDK NIH HHS / United States N01 HC085081 / HC / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States UL1 RR025005 / RR / NCRR NIH HHS / United States N01 AG062101 / AG 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