| Title: | Colocalization of eQTLs with Type 2 Diabetes and Glycemic Traits using Whole-Genome Sequences in Diverse Populations from NHLBI Trans-Omics in Precision Medicine (TOPMed) Program |
| Journal: | Diabetes |
| Published: | 11 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42274313/ |
| DOI: | https://doi.org/10.2337/db25-0557 |
| URL: | https://digitalcommons.library.tmc.edu/context/baylor_docs/article/8578/viewcontent/db250557.pdf |
Publication 21456
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Abstract
Large-scale multiancestry genome-wide association studies have identified hundreds of loci associated with type 2 diabetes (T2D) and glycemic traits, yet imputed genotyping arrays limit the detection of low-frequency and rare variants. Whole-genome sequencing (WGS) offers a more complete view of genetic variation, especially across diverse populations. We analyzed high-coverage (38×) WGS data from 21,913 T2D case subjects, 61,036 control subjects, and up to 50,011 individuals with no diabetes with fasting glucose, fasting insulin, and HbA1c from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine Program. We performed single-variant association testing, conditional analysis, fine-mapping, and Bayesian colocalization to identify genetic signals and assess regulatory relevance in diabetes-related tissues. We identified 76 distinct association signals across 34 loci, including novel variants at DUSP9 for T2D, and ROBO1, NDN, and MYT1 for HbA1c. Fine-mapping narrowed credible sets and improved causal variant resolution. Colocalization highlighted 80 expression signals in diabetes-related tissues, linking genetic associations to functional regulatory mechanisms. Our findings demonstrate the utility of WGS to uncover novel variants in diverse populations, enhance locus resolution, and link regulatory variation to disease-relevant tissues. This work refines the genetic architecture of T2D and glycemic traits and supports precision medicine efforts targeting diverse populations.</p>
ARTICLE HIGHLIGHTS: We aimed to improve understanding of the genetic architecture of type 2 diabetes and glycemic traits by leveraging whole-genome sequencing in diverse populations. Our goal was to identify novel variants, refine known loci, and link genetic signals to regulatory mechanisms through colocalization with expression quantitative trait loci. We discovered novel variants, significantly improved fine-mapping resolution, and identified 80 regulatory colocalization signals in diabetes-relevant tissues. These findings support precision medicine approaches by connecting genetic variation to functional biology in type 2 diabetes.</p>
14 Keywords
- Blood Glucose
- Diabetes Mellitus, Type 2
- Female
- Genome-Wide Association Study
- Glycated Hemoglobin
- Humans
- Male
- Middle Aged
- National Heart, Lung, and Blood Institute (U.S.)
- Polymorphism, Single Nucleotide
- Precision Medicine
- Quantitative Trait Loci
- United States
- Whole Genome Sequencing
242 Authors
- Ningyuan Wang
- Daniel A. DiCorpo
- Yixin Zhang
- Erica Kleinbrink
- Donna K. Arnett
- John Barnard
- John Blangero
- Donald W. Bowden
- April P. Carson
- Yii-Der Ida Chen
- Mina K. Chung
- Joanne E. Curran
- Dawood Darbar
- Ravindranath Duggirala
- Patrick T. Ellinor
- Diane Fatkin
- Myriam Fornage
- Nancy Heard-Costa
- Jiang He
- Lifang Hou
- Sharon L.R. Kardia
- Charles Kooperberg
- Ruth J.F. Loos
- David D. McManus
- Braxton D. Mitchell
- Ryan L. Minster
- Kari E. North
- Bruce M. Psaty
- Laura M. Raffield
- Susan Redline
- Stephen S. Rich
- Dan Roden
- Jerome I. Rotter
- Moore B. Shoemaker
- Jonathan D. Smith
- David R. Van Wagoner
- Francois Aguet
- Kristin Ardlie
- Joshua C. Bis
- Jennifer A. Brody
- Brian E. Cade
- Clary B. Clish
- Paul S. de Vries
- James S. Floyd
- Barry I. Freedman
- Stacey Gabriel
- Robert E. Gerzsten
- Mark O. Goodarzi
- Charles Gu
- Xiuqing Guo
- Namrata Gupta
- Susan R. Heckbert
- Sarah Hsu
- Yi-Jen Hung
- Rita R. Kalyani
- Tanika N. Kelly
- Gregory L. Kinney
- Changwei Li
- Simin Liu
- Yongmei Liu
- Donald M. Lloyd-Jones
- JoAnn E. Manson
- Rasika A. Mathias
- Josep M. Mercader
- Alanna C. Morrison
- Take Naseri
- Suna Onengut
- Nicholette D. Palmer
- Patricia A. Peyser
- Qibin Qi
- Sridharan Raghavan
- Alex P. Reiner
- Mary R. Rooney
- Magdalena Sevilla-Gonzalez
- Chloe Sarnowski
- Joshua D. Smith
- Jennifer A. Smith
- Nicole L. Spartano
- Usman Tahir
- Kent D. Taylor
- Deirdre K. Tobias
- Russel P. Tracy
- Satupa'itea Viali
- Heming Wang
- Alexis C. Wood
- Lisa R. Yanek
- Wei Zhao
- Yinan Zheng
- Josée Dupuis
- Ching-Ti Liu
- Robert Sladek
- Jennifer Wessel
- James B. Meigs
- Alisa K. Manning
- Christine Albert
- Laura Almasy
- Alvaro Alonso
- Seth Ament
- Pramod Anugu
- Dan Arking
- Stella Aslibekyan
- Tim Assimes
- Paul Auer
- John Barnard
- R. Graham Barr
- Terri Beaty
- Diane Becker
- Lewis Becker
- Amber Beitelshees
- Larry Bielak
- Russell Bowler
- Ulrich Broeckel
- Cara Carty
- Richard Casaburi
- Peter Castaldi
- Mark Chaffin
- Yi-Cheng Chang
- Daniel Chasman
- Wei-Min Chen
- Seung Hoan Choi
- Lee-Ming Chuang
- Ren-Hua Chung
- Elaine Cornell
- Carolyn Crandall
- James Crapo
- Jeffrey Curtis
- Coleen Damcott
- Michelle Daya
- Dawn DeMeo
- Ranjan Deka
- Scott Devine
- Qing Duan
- Jon Peter Durda
- Charles Eaton
- Lynette Ekunwe
- Adel El Boueiz
- Charles Farber
- Nora Franceschini
- Mao Fu
- Margery Gass
- Auyon Ghosh
- David Glahn
- Harald Goring
- Jeff Haessler
- Michael Hall
- Daniel Harris
- Nicola L. Hawley
- David Herrington
- Craig Hersh
- Bertha Hidalgo
- James Hixson
- John Hokanson
- Karin Hoth
- Chao (Agnes) Hsiung
- Chii Min Hwu
- Marguerite Ryan Irvin
- Cashell Jaquish
- Andrew Johnson
- Craig Johnson
- Robert Kaplan
- Eimear Kenny
- Michael Kessler
- Wonji Kim
- Holly Kramer
- Christoph Lange
- Ethan Lange
- Cathy Laurie
- Meryl LeBoff
- Wen-Jane Lee
- Dan Levy
- Joshua Lewis
- Xiaohui Li
- Yun Li
- Henry Lin
- Honghuang Lin
- Xihong Lin
- Steven Lubitz
- Kathryn Lunetta
- Michael Mahaney
- Barry Make
- Ani Manichaikul
- Lisa Martin
- Patrick McArdle
- Merry-Lynn McDonald
- Hao Mei
- Yuan-I Min
- Matt Moll
- May Montasser
- Josyf C. Mychaleckyj
- Girish Nadkarni
- Rakhi Naik
- Jeff O'Connell
- Tim O'Connor
- Heather Ochs-Balcom
- James Pankow
- Gina Peloso
- Juan Manuel Peralta
- Marco Perez
- James Perry
- Ulrike Peters
- Lawrence S. Phillips
- Wendy Post
- Michael Preuss
- Dandi Qiao
- D.C. Rao
- Laura Rasmussen-Torvik
- Aakrosh Ratan
- Carolina Roselli
- Ingo Ruczinski
- Kathleen Ryan
- Shabnam Salimi
- Kevin Sandow
- Richa Saxena
- Karen Schwander
- Frank Sciurba
- Amol Shetty
- Wayne Hui-Heng Sheu
- Brian Silver
- Nicholas Smith
- Sylvia Smoller
- Tamar Sofer
- Nona Sotoodehnia
- Elizabeth Streeten
- Yun Ju Sung
- Hua Tang
- Margaret Taub
- Simeon Taylor
- Lesley Tinker
- David Tirschwell
- Hemant Tiwari
- Catherine Tong
- Michael Tsai
- Dhananjay Vaidya
- Robert Wallace
- Karol Watson
- Daniel E. Weeks
- Lu-Chen Weng
- Carla Wilson
- Huichun Xu
- Xiaofeng Zhu
- Mariza de Andrade
- Lisa de las Fuentes.
1 Application
| Application ID | Title |
|---|---|
| 42614 | Statistical methods for discovery and validation of associations with cardiovascular and aging traits and their associated risk factors |
Enabling scientific discoveries that improve human health