Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
24183453
TITLE
Inference of the genetic architecture underlying BMI and height with the use of 20,240 sibling pairs.
ABSTRACT
Evidence that complex traits are highly polygenic has been presented by population-based genome-wide association studies (GWASs) through the identification of many significant variants, as well as by family-based de novo sequencing studies indicating that several traits have a large mutational target size. Here, using a third study design, we show results consistent with extreme polygenicity for body mass index (BMI) and height. On a sample of 20,240 siblings (from 9,570 nuclear families), we used a within-family method to obtain narrow-sense heritability estimates of 0.42 (SE = 0.17, p = 0.01) and 0.69 (SE = 0.14, p = 6 × 10(-)(7)) for BMI and height, respectively, after adjusting for covariates. The genomic inflation factors from locus-specific linkage analysis were 1.69 (SE = 0.21, p = 0.04) for BMI and 2.18 (SE = 0.21, p = 2 × 10(-10)) for height. This inflation is free of confounding and congruent with polygenicity, consistent with observations of ever-increasing genomic-inflation factors from GWASs with large sample sizes, implying that those signals are due to true genetic signals across the genome rather than population stratification. We also demonstrate that the distribution of the observed test statistics is consistent with both rare and common variants underlying a polygenic architecture and that previous reports of linkage signals in complex traits are probably a consequence of polygenic architecture rather than the segregation of variants with large effects. The convergent empirical evidence from GWASs, de novo studies, and within-family segregation implies that family-based sequencing studies for complex traits require very large sample sizes because the effects of causal variants are small on average.
Copyright 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
DATE PUBLISHED
2013 Nov 7
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2013/08/07
revised 2013/09/25
accepted 2013/10/03
aheadofprint 2013/10/31
entrez 2013/11/05 06:00
pubmed 2013/11/05 06:00
medline 2014/01/01 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Hemani G Hemani Gibran G The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; The University of Queensland, Queensland Brain Institute, Brisbane, QLD 4027, Australia.
Yang J Yang Jian J
Vinkhuyzen A Vinkhuyzen Anna A
Powell JE Powell Joseph E JE
Willemsen G Willemsen Gonneke G
Hottenga JJ Hottenga Jouke-Jan JJ
Abdellaoui A Abdellaoui Abdel A
Mangino M Mangino Massimo M
Valdes AM Valdes Ana M AM
Medland SE Medland Sarah E SE
Madden PA Madden Pamela A PA
Heath AC Heath Andrew C AC
Henders AK Henders Anjali K AK
Nyholt DR Nyholt Dale R DR
de Geus EJ de Geus Eco J C EJ
Magnusson PK Magnusson Patrik K E PK
Ingelsson E Ingelsson Erik E
Montgomery GW Montgomery Grant W GW
Spector TD Spector Timothy D TD
Boomsma DI Boomsma Dorret I DI
Pedersen NL Pedersen Nancy L NL
Martin NG Martin Nicholas G NG
Visscher PM Visscher Peter M PM
INVESTIGATORS
JOURNAL
VOLUME: 93
ISSUE: 5
TITLE: American journal of human genetics
ISOABBREVIATION: Am. J. Hum. Genet.
YEAR: 2013
MONTH: Nov
DAY: 7
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1537-6605
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Am J Hum Genet
COUNTRY: United States
ISSNLINKING: 0002-9297
NLMUNIQUEID: 0370475
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
1RC2 MH089995-01 NIMH NIH HHS United States
1RC2MH089951-01 NIMH NIH HHS United States
AA014041 NIAAA NIH HHS United States
AA07535 NIAAA NIH HHS United States
AA10248 NIAAA NIH HHS United States
AA13320 NIAAA NIH HHS United States
AA13321 NIAAA NIH HHS United States
AA13326 NIAAA NIH HHS United States
DA12854 NIDA NIH HHS United States
DK U01-066134 NIDDK NIH HHS United States
GM075091 NIGMS NIH HHS United States
GM099568 NIGMS NIH HHS United States
N01-HC-25195 NHLBI NIH HHS United States
N02-HL-64278 NHLBI NIH HHS United States
R01 GM075091 NIGMS NIH HHS United States
R01D0042157-01A PHS HHS United States
U24 MH068457-06 NIMH NIH HHS United States
Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Alleles
Body Height genetics
Body Mass Index genetics
Female genetics
Genetic Linkage genetics
Genetics, Population genetics
Genome, Human genetics
Genotype genetics
Humans genetics
Male genetics
Models, Genetic genetics
Phenotype genetics
Polymorphism, Single Nucleotide genetics
Quantitative Trait Loci genetics
Quantitative Trait, Heritable genetics
Siblings genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
OTHERID SOURCE
PMC3965855 NLM