Genome-wide association analysis of metabolic syndrome quantitative traits in the GENNID multiethnic family study

Jia Wan ,Stephen Freedland ,John B Buse ,Wilfred Y Fujimoto ,Steven E Kahn ,P Behn ,Steven C Elbein ,Craig L Hanis ,Jeanne C Beck ,Eric Boerwinkle ,Trina M Norden-Krichmar,Stephanie A Santorico,Jill M Norris ,David A Ehrmann ,Leslie J Raffel ,R.a Mulivor ,Deborah Goodman ,M A Permutt ,Emileigh Willems ,Ralph A Defronzo ,David C Robbins ,Karen L Edwards

doi:10.1186/s13098-021-00670-3

Jia Wan , Stephen Freedland + Show 20 more

Open Access

https://doi.org/10.1186/s13098-021-00670-3

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Abstract

BackgroundTo identify genetic associations of quantitative metabolic syndrome (MetS) traits and characterize heterogeneity across ethnic groups.MethodsData was collected from GENetics of Noninsulin dependent Diabetes Mellitus (GENNID), a multiethnic resource of Type 2 diabetic families and included 1520 subjects in 259 African-American, European-American, Japanese-Americans, and Mexican-American families. We focused on eight MetS traits: weight, waist circumference, systolic and diastolic blood pressure, high-density lipoprotein, triglycerides, fasting glucose, and insulin. Using genotyped and imputed data from Illumina’s Multiethnic array, we conducted genome-wide association analyses with linear mixed models for all ethnicities, except for the smaller Japanese-American group, where we used additive genetic models with gene-dropping.ResultsFindings included ethnic-specific genetic associations and heterogeneity across ethnicities. Most significant associations were outside our candidate linkage regions and were coincident within a gene or intergenic region, with two exceptions in European-American families: (a) within previously identified linkage region on chromosome 2, two significant GLI2-TFCP2L1 associations with weight, and (b) one chromosome 11 variant near CADM1-LINC00900 with pleiotropic blood pressure effects.ConclusionsThis multiethnic family study found genetic heterogeneity and coincident associations (with one case of pleiotropy), highlighting the importance of including diverse populations in genetic research and illustrating the complex genetic architecture underlying MetS.

Highlights

To identify genetic associations of quantitative metabolic syndrome (MetS) traits and characterize heterogeneity across ethnic groups
After quality control (QC), there was a similar number of Quantita‐ tive trait nucleotide (QTN) for Mexican American (MA), AA, and European American (EA) families—about 731 K, 710 K, and 686 K QTNs, respectively
The lower number of QTNs among Japanese American (JA) families was due to the removal of a large number of monomorphic markers, which may suggest a lower

Summary

Introduction

To identify genetic associations of quantitative metabolic syndrome (MetS) traits and characterize heterogeneity across ethnic groups. Family-based studies have been a primary approach for identifying genetic influences on a range of disease and still offer many advantages [16, 17] including being robust to confounding due to underlying population structure and phenotype model misspecifications, using pedigree structures and information on related individuals to detect genotyping errors [16], and having more power to detect rare variants [16, 17]. Accumulating evidence suggests that the specific combination of traits may matter and could explain the large number of variants associated with MetS [29, 30]. Obesity, high TG, high fasting insulin, and low HDL are associated with MIP1, MC4R, and PRKD1, yet when these same traits are combined with hypertension, they are associated with FTO and TMEM18 [8]

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