Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms

نویسندگان

  • Momoko Horikoshi
  • Lorenzo Pasquali
  • Steven Wiltshire
  • Jeroen R. Huyghe
  • Anubha Mahajan
  • Jennifer L. Asimit
  • Teresa Ferreira
  • Adam E. Locke
  • Neil R. Robertson
  • Xu Wang
  • Xueling Sim
  • Hayato Fujita
  • Kazuo Hara
  • Robin Young
  • Weihua Zhang
  • Sungkyoung Choi
  • Han Chen
  • Ismeet Kaur
  • Fumihiko Takeuchi
  • Pierre Fontanillas
  • Dorothée Thuillier
  • Loic Yengo
  • Jennifer E. Below
  • Claudia H.T. Tam
  • Ying Wu
  • Gonçalo Abecasis
  • David Altshuler
  • Graeme I. Bell
  • John Blangero
  • Noél P. Burtt
  • Ravindranath Duggirala
  • Jose C. Florez
  • Craig L. Hanis
  • Mark Seielstad
  • Gil Atzmon
  • Juliana C.N. Chan
  • Ronald C.W. Ma
  • Philippe Froguel
  • James G. Wilson
  • Dwaipayan Bharadwaj
  • Josee Dupuis
  • James B. Meigs
  • Yoon Shin Cho
  • Taesung Park
  • Jaspal S. Kooner
  • John C. Chambers
  • Danish Saleheen
  • Takashi Kadowaki
  • E. Shyong Tai
  • Karen L. Mohlke
  • Nancy J. Cox
  • Jorge Ferrer
  • Eleftheria Zeggini
  • Norihiro Kato
  • Yik Ying Teo
  • Michael Boehnke
  • Mark I. McCarthy
  • Andrew P. Morris
چکیده

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Erratum to: Fine Mapping of Type 2 Diabetes Susceptibility Loci

Genome-wide association studies of type 2 diabetes have been extremely successful in discovering loci that contribute genetic effects to susceptibility to the disease. However, at the vast majority of these loci, the variants and transcripts through which these effects on type 2 diabetes are mediated are unknown, limiting progress in defining the pathophysiological basis of the disease. In this...

متن کامل

Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (A...

متن کامل

Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G

OBJECTIVES Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk fo...

متن کامل

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

The majority of GWAS of T2D susceptibility have been undertaken in populations of European ancestry1–5, predominantly because of existing infrastructure, sample availability and relatively poor coverage by many of the earliest genome-wide genotyping arrays of common genetic variation in other major ethnic groups6. However, populations of European ancestry constitute only a subset of human genet...

متن کامل

Integration of human pancreatic islet genomic data refines 1 regulatory mechanisms at Type 2 Diabetes susceptibility loci

24 Human genetic studies have emphasised the dominant contribution of 25 pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, 26 limited annotation of the islet epigenome has constrained efforts to define the 27 molecular mechanisms mediating the, largely regulatory, signals revealed by 28 Genome-Wide Association Studies (GWAS). We characterised patterns of 29 chromati...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 25  شماره 

صفحات  -

تاریخ انتشار 2016