Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees

Goo Jun, Alisa Manning, Marcio Almeida, Matthew Zawistowski, Andrew R. Wood, Tanya M. Teslovich, Christian Fuchsberger, Shuang Feng, Pablo Cingolani, Kyle J. Gaulton, Thomas Dyer, Thomas W. Blackwell, Han Chen, Peter S. Chines, Sungkyoung Choi, Claire Churchhouse, Pierre Fontanillas, Ryan King, Sung Young Lee, Stephen E. LincolnVasily Trubetskoy, Mark DePristo, Tasha Fingerlin, Robert Grossman, Jason Grundstad, Alison Heath, Jayoun Kim, Young Jin Kim, Jason Laramie, Jaehoon Lee, Heng Li, Xuanyao Liu, Oren Livne, Adam E. Locke, Julian Maller, Alexander Mazur, Andrew P. Morris, Toni I. Pollin, Derek Ragona, David Reich, Manuel A. Rivas, Laura J. Scott, Xueling Sim, Rick G. Tearle, Yik Ying Teo, Amy L. Williams, Sebastian Zöllner, Joanne E Curran, Juan Peralta, Beena Akolkar, Graeme I. Bell, Noël P. Burtt, Nancy J. Cox, Jose C. Florez, Craig L. Hanis, Catherine McKeon, Karen L. Mohlke, Mark Seielstad, James G. Wilson, Gil Atzmon, Jennifer E. Below, Josée Dupuis, Dan L. Nicolae, Donna Lehman, Taesung Park, Sungho Won, Robert Sladek, David Altshuler, Mark I. McCarthy, Ravindranath Duggirala, Michael Boehnke, Timothy M. Frayling, Gonçalo R. Abecasis, John C Blangero

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.

Original languageEnglish (US)
Pages (from-to)379-384
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number2
StatePublished - Jan 9 2017


  • EQTL
  • Genetics
  • Rare variants
  • Sequencing
  • Type 2 diabetes

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees'. Together they form a unique fingerprint.

Cite this