Dataset Information

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

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.

SUBMITTER: Liu CT

PROVIDER: S-EPMC5005440 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Liu Ching-Ti CT Raghavan Sridharan S Maruthur Nisa N Kabagambe Edmond Kato EK Hong Jaeyoung J Ng Maggie C Y MC Hivert Marie-France MF Lu Yingchang Y An Ping P Bentley Amy R AR Drolet Anne M AM Gaulton Kyle J KJ Guo Xiuqing X Armstrong Loren L LL Irvin Marguerite R MR Li Man M Lipovich Leonard L Rybin Denis V DV Taylor Kent D KD Agyemang Charles C Palmer Nicholette D ND Cade Brian E BE Chen Wei-Min WM Dauriz Marco M Delaney Joseph A C JA Edwards Todd L TL Evans Daniel S DS Evans Michele K MK Lange Leslie A LA Leong Aaron A Liu Jingmin J Liu Yongmei Y Nayak Uma U Patel Sanjay R SR Porneala Bianca C BC Rasmussen-Torvik Laura J LJ Snijder Marieke B MB Stallings Sarah C SC Tanaka Toshiko T Yanek Lisa R LR Zhao Wei W Becker Diane M DM Bielak Lawrence F LF Biggs Mary L ML Bottinger Erwin P EP Bowden Donald W DW Chen Guanjie G Correa Adolfo A Couper David J DJ Crawford Dana C DC Cushman Mary M Eicher John D JD Fornage Myriam M Franceschini Nora N Fu Yi-Ping YP Goodarzi Mark O MO Gottesman Omri O Hara Kazuo K Harris Tamara B TB Jensen Richard A RA Johnson Andrew D AD Jhun Min A MA Karter Andrew J AJ Keller Margaux F MF Kho Abel N AN Kizer Jorge R JR Krauss Ronald M RM Langefeld Carl D CD Li Xiaohui X Liang Jingling J Liu Simin S Lowe William L WL Mosley Thomas H TH North Kari E KE Pacheco Jennifer A JA Peyser Patricia A PA Patrick Alan L AL Rice Kenneth M KM Selvin Elizabeth E Sims Mario M Smith Jennifer A JA Tajuddin Salman M SM Vaidya Dhananjay D Wren Mary P MP Yao Jie J Zhu Xiaofeng X Ziegler Julie T JT Zmuda Joseph M JM Zonderman Alan B AB Zwinderman Aeilko H AH Adeyemo Adebowale A Boerwinkle Eric E Ferrucci Luigi L Hayes M Geoffrey MG Kardia Sharon L R SL Miljkovic Iva I Pankow James S JS Rotimi Charles N CN Sale Michele M MM Wagenknecht Lynne E LE Arnett Donna K DK Chen Yii-Der Ida YD Nalls Michael A MA Province Michael A MA Kao W H Linda WH Siscovick David S DS Psaty Bruce M BM Wilson James G JG Loos Ruth J F RJ Dupuis Josée J Rich Stephen S SS Florez Jose C JC Rotter Jerome I JI Morris Andrew P AP Meigs James B JB

American journal of human genetics 20160616 1

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 ...[more]

PMID: 27321945

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Project description:BACKGROUND:Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. OBJECTIVE:We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus. DESIGN:Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations. RESULTS:Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance. CONCLUSION:The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

Dataset Information

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

Publications

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

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