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. Lincoln & 54 others Vasily 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 M Lehman, Taesung Park, Sungho Won, Robert Sladek, David Altshuler, Mark I. McCarthy, Ravindranath Duggirala, Michael Boehnke, Timothy M. Frayling, Gonçalo R. Abecasis, John Blangero

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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
Volume115
Issue number2
DOIs
StatePublished - Jan 9 2017

Fingerprint

Pedigree
Type 2 Diabetes Mellitus
Quantitative Trait Loci
Fasting
Alleles
Genome
Insulin
Gene Expression
Glucose
Population

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees. / Jun, Goo; Manning, Alisa; Almeida, Marcio; Zawistowski, Matthew; Wood, Andrew R.; Teslovich, Tanya M.; Fuchsberger, Christian; Feng, Shuang; Cingolani, Pablo; Gaulton, Kyle J.; Dyer, Thomas; Blackwell, Thomas W.; Chen, Han; Chines, Peter S.; Choi, Sungkyoung; Churchhouse, Claire; Fontanillas, Pierre; King, Ryan; Lee, Sung Young; Lincoln, Stephen E.; Trubetskoy, Vasily; DePristo, Mark; Fingerlin, Tasha; Grossman, Robert; Grundstad, Jason; Heath, Alison; Kim, Jayoun; Kim, Young Jin; Laramie, Jason; Lee, Jaehoon; Li, Heng; Liu, Xuanyao; Livne, Oren; Locke, Adam E.; Maller, Julian; Mazur, Alexander; Morris, Andrew P.; Pollin, Toni I.; Ragona, Derek; Reich, David; Rivas, Manuel A.; Scott, Laura J.; Sim, Xueling; Tearle, Rick G.; Teo, Yik Ying; Williams, Amy L.; Zöllner, Sebastian; Curran, Joanne E.; Peralta, Juan; Akolkar, Beena; Bell, Graeme I.; Burtt, Noël P.; Cox, Nancy J.; Florez, Jose C.; Hanis, Craig L.; McKeon, Catherine; Mohlke, Karen L.; Seielstad, Mark; Wilson, James G.; Atzmon, Gil; Below, Jennifer E.; Dupuis, Josée; Nicolae, Dan L.; Lehman, Donna M; Park, Taesung; Won, Sungho; Sladek, Robert; Altshuler, David; McCarthy, Mark I.; Duggirala, Ravindranath; Boehnke, Michael; Frayling, Timothy M.; Abecasis, Gonçalo R.; Blangero, John.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 2, 09.01.2017, p. 379-384.

Research output: Contribution to journalArticle

Jun, G, Manning, A, Almeida, M, Zawistowski, M, Wood, AR, Teslovich, TM, Fuchsberger, C, Feng, S, Cingolani, P, Gaulton, KJ, Dyer, T, Blackwell, TW, Chen, H, Chines, PS, Choi, S, Churchhouse, C, Fontanillas, P, King, R, Lee, SY, Lincoln, SE, Trubetskoy, V, DePristo, M, Fingerlin, T, Grossman, R, Grundstad, J, Heath, A, Kim, J, Kim, YJ, Laramie, J, Lee, J, Li, H, Liu, X, Livne, O, Locke, AE, Maller, J, Mazur, A, Morris, AP, Pollin, TI, Ragona, D, Reich, D, Rivas, MA, Scott, LJ, Sim, X, Tearle, RG, Teo, YY, Williams, AL, Zöllner, S, Curran, JE, Peralta, J, Akolkar, B, Bell, GI, Burtt, NP, Cox, NJ, Florez, JC, Hanis, CL, McKeon, C, Mohlke, KL, Seielstad, M, Wilson, JG, Atzmon, G, Below, JE, Dupuis, J, Nicolae, DL, Lehman, DM, Park, T, Won, S, Sladek, R, Altshuler, D, McCarthy, MI, Duggirala, R, Boehnke, M, Frayling, TM, Abecasis, GR & Blangero, J 2017, 'Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 2, pp. 379-384. https://doi.org/10.1073/pnas.1705859115
Jun, Goo ; Manning, Alisa ; Almeida, Marcio ; Zawistowski, Matthew ; Wood, Andrew R. ; Teslovich, Tanya M. ; Fuchsberger, Christian ; Feng, Shuang ; Cingolani, Pablo ; Gaulton, Kyle J. ; Dyer, Thomas ; Blackwell, Thomas W. ; Chen, Han ; Chines, Peter S. ; Choi, Sungkyoung ; Churchhouse, Claire ; Fontanillas, Pierre ; King, Ryan ; Lee, Sung Young ; Lincoln, Stephen E. ; Trubetskoy, Vasily ; DePristo, Mark ; Fingerlin, Tasha ; Grossman, Robert ; Grundstad, Jason ; Heath, Alison ; Kim, Jayoun ; Kim, Young Jin ; Laramie, Jason ; Lee, Jaehoon ; Li, Heng ; Liu, Xuanyao ; Livne, Oren ; Locke, Adam E. ; Maller, Julian ; Mazur, Alexander ; Morris, Andrew P. ; Pollin, Toni I. ; Ragona, Derek ; Reich, David ; Rivas, Manuel A. ; Scott, Laura J. ; Sim, Xueling ; Tearle, Rick G. ; Teo, Yik Ying ; Williams, Amy L. ; Zöllner, Sebastian ; Curran, Joanne E. ; Peralta, Juan ; Akolkar, Beena ; Bell, Graeme I. ; Burtt, Noël P. ; Cox, Nancy J. ; Florez, Jose C. ; Hanis, Craig L. ; McKeon, Catherine ; Mohlke, Karen L. ; Seielstad, Mark ; Wilson, James G. ; Atzmon, Gil ; Below, Jennifer E. ; Dupuis, Josée ; Nicolae, Dan L. ; Lehman, Donna M ; Park, Taesung ; Won, Sungho ; Sladek, Robert ; Altshuler, David ; McCarthy, Mark I. ; Duggirala, Ravindranath ; Boehnke, Michael ; Frayling, Timothy M. ; Abecasis, Gonçalo R. ; Blangero, John. / Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 115, No. 2. pp. 379-384.
@article{3fdbfc6d31e04d4abb19089be5eba6c3,
title = "Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees",
abstract = "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.",
keywords = "EQTL, Genetics, Rare variants, Sequencing, Type 2 diabetes",
author = "Goo Jun and Alisa Manning and Marcio Almeida and Matthew Zawistowski and Wood, {Andrew R.} and Teslovich, {Tanya M.} and Christian Fuchsberger and Shuang Feng and Pablo Cingolani and Gaulton, {Kyle J.} and Thomas Dyer and Blackwell, {Thomas W.} and Han Chen and Chines, {Peter S.} and Sungkyoung Choi and Claire Churchhouse and Pierre Fontanillas and Ryan King and Lee, {Sung Young} and Lincoln, {Stephen E.} and Vasily Trubetskoy and Mark DePristo and Tasha Fingerlin and Robert Grossman and Jason Grundstad and Alison Heath and Jayoun Kim and Kim, {Young Jin} and Jason Laramie and Jaehoon Lee and Heng Li and Xuanyao Liu and Oren Livne and Locke, {Adam E.} and Julian Maller and Alexander Mazur and Morris, {Andrew P.} and Pollin, {Toni I.} and Derek Ragona and David Reich and Rivas, {Manuel A.} and Scott, {Laura J.} and Xueling Sim and Tearle, {Rick G.} and Teo, {Yik Ying} and Williams, {Amy L.} and Sebastian Z{\"o}llner and Curran, {Joanne E.} and Juan Peralta and Beena Akolkar and Bell, {Graeme I.} and Burtt, {No{\"e}l P.} and Cox, {Nancy J.} and Florez, {Jose C.} and Hanis, {Craig L.} and Catherine McKeon and Mohlke, {Karen L.} and Mark Seielstad and Wilson, {James G.} and Gil Atzmon and Below, {Jennifer E.} and Jos{\'e}e Dupuis and Nicolae, {Dan L.} and Lehman, {Donna M} and Taesung Park and Sungho Won and Robert Sladek and David Altshuler and McCarthy, {Mark I.} and Ravindranath Duggirala and Michael Boehnke and Frayling, {Timothy M.} and Abecasis, {Gon{\cc}alo R.} and John Blangero",
year = "2017",
month = "1",
day = "9",
doi = "10.1073/pnas.1705859115",
language = "English (US)",
volume = "115",
pages = "379--384",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "2",

}

TY - JOUR

T1 - Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees

AU - Jun, Goo

AU - Manning, Alisa

AU - Almeida, Marcio

AU - Zawistowski, Matthew

AU - Wood, Andrew R.

AU - Teslovich, Tanya M.

AU - Fuchsberger, Christian

AU - Feng, Shuang

AU - Cingolani, Pablo

AU - Gaulton, Kyle J.

AU - Dyer, Thomas

AU - Blackwell, Thomas W.

AU - Chen, Han

AU - Chines, Peter S.

AU - Choi, Sungkyoung

AU - Churchhouse, Claire

AU - Fontanillas, Pierre

AU - King, Ryan

AU - Lee, Sung Young

AU - Lincoln, Stephen E.

AU - Trubetskoy, Vasily

AU - DePristo, Mark

AU - Fingerlin, Tasha

AU - Grossman, Robert

AU - Grundstad, Jason

AU - Heath, Alison

AU - Kim, Jayoun

AU - Kim, Young Jin

AU - Laramie, Jason

AU - Lee, Jaehoon

AU - Li, Heng

AU - Liu, Xuanyao

AU - Livne, Oren

AU - Locke, Adam E.

AU - Maller, Julian

AU - Mazur, Alexander

AU - Morris, Andrew P.

AU - Pollin, Toni I.

AU - Ragona, Derek

AU - Reich, David

AU - Rivas, Manuel A.

AU - Scott, Laura J.

AU - Sim, Xueling

AU - Tearle, Rick G.

AU - Teo, Yik Ying

AU - Williams, Amy L.

AU - Zöllner, Sebastian

AU - Curran, Joanne E.

AU - Peralta, Juan

AU - Akolkar, Beena

AU - Bell, Graeme I.

AU - Burtt, Noël P.

AU - Cox, Nancy J.

AU - Florez, Jose C.

AU - Hanis, Craig L.

AU - McKeon, Catherine

AU - Mohlke, Karen L.

AU - Seielstad, Mark

AU - Wilson, James G.

AU - Atzmon, Gil

AU - Below, Jennifer E.

AU - Dupuis, Josée

AU - Nicolae, Dan L.

AU - Lehman, Donna M

AU - Park, Taesung

AU - Won, Sungho

AU - Sladek, Robert

AU - Altshuler, David

AU - McCarthy, Mark I.

AU - Duggirala, Ravindranath

AU - Boehnke, Michael

AU - Frayling, Timothy M.

AU - Abecasis, Gonçalo R.

AU - Blangero, John

PY - 2017/1/9

Y1 - 2017/1/9

N2 - 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.

AB - 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.

KW - EQTL

KW - Genetics

KW - Rare variants

KW - Sequencing

KW - Type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85040252130&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040252130&partnerID=8YFLogxK

U2 - 10.1073/pnas.1705859115

DO - 10.1073/pnas.1705859115

M3 - Article

VL - 115

SP - 379

EP - 384

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 2

ER -