---
_id: '7722'
abstract:
- lang: eng
  text: We develop a Bayesian mixed linear model that simultaneously estimates single-nucleotide
    polymorphism (SNP)-based heritability, polygenicity (proportion of SNPs with nonzero
    effects), and the relationship between SNP effect size and minor allele frequency
    for complex traits in conventionally unrelated individuals using genome-wide SNP
    data. We apply the method to 28 complex traits in the UK Biobank data (N = 126,752)
    and show that on average, 6% of SNPs have nonzero effects, which in total explain
    22% of phenotypic variance. We detect significant (P < 0.05/28) signatures of
    natural selection in the genetic architecture of 23 traits, including reproductive,
    cardiovascular, and anthropometric traits, as well as educational attainment.
    The significant estimates of the relationship between effect size and minor allele
    frequency in complex traits are consistent with a model of negative (or purifying)
    selection, as confirmed by forward simulation. We conclude that negative selection
    acts pervasively on the genetic variants associated with human complex traits.
article_processing_charge: No
article_type: original
author:
- first_name: Jian
  full_name: Zeng, Jian
  last_name: Zeng
- first_name: Ronald
  full_name: de Vlaming, Ronald
  last_name: de Vlaming
- first_name: Yang
  full_name: Wu, Yang
  last_name: Wu
- first_name: Matthew Richard
  full_name: Robinson, Matthew Richard
  id: E5D42276-F5DA-11E9-8E24-6303E6697425
  last_name: Robinson
  orcid: 0000-0001-8982-8813
- first_name: Luke R.
  full_name: Lloyd-Jones, Luke R.
  last_name: Lloyd-Jones
- first_name: Loic
  full_name: Yengo, Loic
  last_name: Yengo
- first_name: Chloe X.
  full_name: Yap, Chloe X.
  last_name: Yap
- first_name: Angli
  full_name: Xue, Angli
  last_name: Xue
- first_name: Julia
  full_name: Sidorenko, Julia
  last_name: Sidorenko
- first_name: Allan F.
  full_name: McRae, Allan F.
  last_name: McRae
- first_name: Joseph E.
  full_name: Powell, Joseph E.
  last_name: Powell
- first_name: Grant W.
  full_name: Montgomery, Grant W.
  last_name: Montgomery
- first_name: Andres
  full_name: Metspalu, Andres
  last_name: Metspalu
- first_name: Tonu
  full_name: Esko, Tonu
  last_name: Esko
- first_name: Greg
  full_name: Gibson, Greg
  last_name: Gibson
- first_name: Naomi R.
  full_name: Wray, Naomi R.
  last_name: Wray
- first_name: Peter M.
  full_name: Visscher, Peter M.
  last_name: Visscher
- first_name: Jian
  full_name: Yang, Jian
  last_name: Yang
citation:
  ama: Zeng J, de Vlaming R, Wu Y, et al. Signatures of negative selection in the
    genetic architecture of human complex traits. <i>Nature Genetics</i>. 2018;50(5):746-753.
    doi:<a href="https://doi.org/10.1038/s41588-018-0101-4">10.1038/s41588-018-0101-4</a>
  apa: Zeng, J., de Vlaming, R., Wu, Y., Robinson, M. R., Lloyd-Jones, L. R., Yengo,
    L., … Yang, J. (2018). Signatures of negative selection in the genetic architecture
    of human complex traits. <i>Nature Genetics</i>. Springer Nature. <a href="https://doi.org/10.1038/s41588-018-0101-4">https://doi.org/10.1038/s41588-018-0101-4</a>
  chicago: Zeng, Jian, Ronald de Vlaming, Yang Wu, Matthew Richard Robinson, Luke
    R. Lloyd-Jones, Loic Yengo, Chloe X. Yap, et al. “Signatures of Negative Selection
    in the Genetic Architecture of Human Complex Traits.” <i>Nature Genetics</i>.
    Springer Nature, 2018. <a href="https://doi.org/10.1038/s41588-018-0101-4">https://doi.org/10.1038/s41588-018-0101-4</a>.
  ieee: J. Zeng <i>et al.</i>, “Signatures of negative selection in the genetic architecture
    of human complex traits,” <i>Nature Genetics</i>, vol. 50, no. 5. Springer Nature,
    pp. 746–753, 2018.
  ista: Zeng J, de Vlaming R, Wu Y, Robinson MR, Lloyd-Jones LR, Yengo L, Yap CX,
    Xue A, Sidorenko J, McRae AF, Powell JE, Montgomery GW, Metspalu A, Esko T, Gibson
    G, Wray NR, Visscher PM, Yang J. 2018. Signatures of negative selection in the
    genetic architecture of human complex traits. Nature Genetics. 50(5), 746–753.
  mla: Zeng, Jian, et al. “Signatures of Negative Selection in the Genetic Architecture
    of Human Complex Traits.” <i>Nature Genetics</i>, vol. 50, no. 5, Springer Nature,
    2018, pp. 746–53, doi:<a href="https://doi.org/10.1038/s41588-018-0101-4">10.1038/s41588-018-0101-4</a>.
  short: J. Zeng, R. de Vlaming, Y. Wu, M.R. Robinson, L.R. Lloyd-Jones, L. Yengo,
    C.X. Yap, A. Xue, J. Sidorenko, A.F. McRae, J.E. Powell, G.W. Montgomery, A. Metspalu,
    T. Esko, G. Gibson, N.R. Wray, P.M. Visscher, J. Yang, Nature Genetics 50 (2018)
    746–753.
date_created: 2020-04-30T10:44:57Z
date_published: 2018-04-16T00:00:00Z
date_updated: 2021-01-12T08:15:06Z
day: '16'
doi: 10.1038/s41588-018-0101-4
extern: '1'
intvolume: '        50'
issue: '5'
language:
- iso: eng
month: '04'
oa_version: None
page: 746-753
publication: Nature Genetics
publication_identifier:
  issn:
  - 1061-4036
  - 1546-1718
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
status: public
title: Signatures of negative selection in the genetic architecture of human complex
  traits
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 50
year: '2018'
...
---
_id: '7737'
abstract:
- lang: eng
  text: Genome-wide association studies (GWAS) have identified thousands of genetic
    variants associated with human complex traits. However, the genes or functional
    DNA elements through which these variants exert their effects on the traits are
    often unknown. We propose a method (called SMR) that integrates summary-level
    data from GWAS with data from expression quantitative trait locus (eQTL) studies
    to identify genes whose expression levels are associated with a complex trait
    because of pleiotropy. We apply the method to five human complex traits using
    GWAS data on up to 339,224 individuals and eQTL data on 5,311 individuals, and
    we prioritize 126 genes (for example, TRAF1 and ANKRD55 for rheumatoid arthritis
    and SNX19 and NMRAL1 for schizophrenia), of which 25 genes are new candidates;
    77 genes are not the nearest annotated gene to the top associated GWAS SNP. These
    genes provide important leads to design future functional studies to understand
    the mechanism whereby DNA variation leads to complex trait variation.
article_processing_charge: No
article_type: original
author:
- first_name: Zhihong
  full_name: Zhu, Zhihong
  last_name: Zhu
- first_name: Futao
  full_name: Zhang, Futao
  last_name: Zhang
- first_name: Han
  full_name: Hu, Han
  last_name: Hu
- first_name: Andrew
  full_name: Bakshi, Andrew
  last_name: Bakshi
- first_name: Matthew Richard
  full_name: Robinson, Matthew Richard
  id: E5D42276-F5DA-11E9-8E24-6303E6697425
  last_name: Robinson
  orcid: 0000-0001-8982-8813
- first_name: Joseph E
  full_name: Powell, Joseph E
  last_name: Powell
- first_name: Grant W
  full_name: Montgomery, Grant W
  last_name: Montgomery
- first_name: Michael E
  full_name: Goddard, Michael E
  last_name: Goddard
- first_name: Naomi R
  full_name: Wray, Naomi R
  last_name: Wray
- first_name: Peter M
  full_name: Visscher, Peter M
  last_name: Visscher
- first_name: Jian
  full_name: Yang, Jian
  last_name: Yang
citation:
  ama: Zhu Z, Zhang F, Hu H, et al. Integration of summary data from GWAS and eQTL
    studies predicts complex trait gene targets. <i>Nature Genetics</i>. 2016;48(5):481-487.
    doi:<a href="https://doi.org/10.1038/ng.3538">10.1038/ng.3538</a>
  apa: Zhu, Z., Zhang, F., Hu, H., Bakshi, A., Robinson, M. R., Powell, J. E., … Yang,
    J. (2016). Integration of summary data from GWAS and eQTL studies predicts complex
    trait gene targets. <i>Nature Genetics</i>. Springer Nature. <a href="https://doi.org/10.1038/ng.3538">https://doi.org/10.1038/ng.3538</a>
  chicago: Zhu, Zhihong, Futao Zhang, Han Hu, Andrew Bakshi, Matthew Richard Robinson,
    Joseph E Powell, Grant W Montgomery, et al. “Integration of Summary Data from
    GWAS and EQTL Studies Predicts Complex Trait Gene Targets.” <i>Nature Genetics</i>.
    Springer Nature, 2016. <a href="https://doi.org/10.1038/ng.3538">https://doi.org/10.1038/ng.3538</a>.
  ieee: Z. Zhu <i>et al.</i>, “Integration of summary data from GWAS and eQTL studies
    predicts complex trait gene targets,” <i>Nature Genetics</i>, vol. 48, no. 5.
    Springer Nature, pp. 481–487, 2016.
  ista: Zhu Z, Zhang F, Hu H, Bakshi A, Robinson MR, Powell JE, Montgomery GW, Goddard
    ME, Wray NR, Visscher PM, Yang J. 2016. Integration of summary data from GWAS
    and eQTL studies predicts complex trait gene targets. Nature Genetics. 48(5),
    481–487.
  mla: Zhu, Zhihong, et al. “Integration of Summary Data from GWAS and EQTL Studies
    Predicts Complex Trait Gene Targets.” <i>Nature Genetics</i>, vol. 48, no. 5,
    Springer Nature, 2016, pp. 481–87, doi:<a href="https://doi.org/10.1038/ng.3538">10.1038/ng.3538</a>.
  short: Z. Zhu, F. Zhang, H. Hu, A. Bakshi, M.R. Robinson, J.E. Powell, G.W. Montgomery,
    M.E. Goddard, N.R. Wray, P.M. Visscher, J. Yang, Nature Genetics 48 (2016) 481–487.
date_created: 2020-04-30T10:50:26Z
date_published: 2016-03-28T00:00:00Z
date_updated: 2021-01-12T08:15:11Z
day: '28'
doi: 10.1038/ng.3538
extern: '1'
intvolume: '        48'
issue: '5'
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1038/ng.3538
month: '03'
oa: 1
oa_version: Published Version
page: 481-487
publication: Nature Genetics
publication_identifier:
  issn:
  - 1061-4036
  - 1546-1718
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
status: public
title: Integration of summary data from GWAS and eQTL studies predicts complex trait
  gene targets
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 48
year: '2016'
...
---
_id: '7742'
abstract:
- lang: eng
  text: Across-nation differences in the mean values for complex traits are common1,2,3,4,5,6,7,8,
    but the reasons for these differences are unknown. Here we find that many independent
    loci contribute to population genetic differences in height and body mass index
    (BMI) in 9,416 individuals across 14 European countries. Using discovery data
    on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling
    pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95%
    CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively,
    reflect population genetic differences. Population genetic divergence differed
    significantly from that in a null model (height, P < 3.94 × 10−8; BMI, P < 5.95
    × 10−4), and we find an among-population genetic correlation for tall and slender
    individuals (r = −0.80, 95% CI = −0.95, −0.60), consistent with correlated selection
    for both phenotypes. Observed differences in height among populations reflected
    the predicted genetic means (r = 0.51; P < 0.001), but environmental differences
    across Europe masked genetic differentiation for BMI (P < 0.58).
article_processing_charge: No
article_type: original
author:
- first_name: Matthew Richard
  full_name: Robinson, Matthew Richard
  id: E5D42276-F5DA-11E9-8E24-6303E6697425
  last_name: Robinson
  orcid: 0000-0001-8982-8813
- first_name: Gibran
  full_name: Hemani, Gibran
  last_name: Hemani
- first_name: Carolina
  full_name: Medina-Gomez, Carolina
  last_name: Medina-Gomez
- first_name: Massimo
  full_name: Mezzavilla, Massimo
  last_name: Mezzavilla
- first_name: Tonu
  full_name: Esko, Tonu
  last_name: Esko
- first_name: Konstantin
  full_name: Shakhbazov, Konstantin
  last_name: Shakhbazov
- first_name: Joseph E
  full_name: Powell, Joseph E
  last_name: Powell
- first_name: Anna
  full_name: Vinkhuyzen, Anna
  last_name: Vinkhuyzen
- first_name: Sonja I
  full_name: Berndt, Sonja I
  last_name: Berndt
- first_name: Stefan
  full_name: Gustafsson, Stefan
  last_name: Gustafsson
- first_name: Anne E
  full_name: Justice, Anne E
  last_name: Justice
- first_name: Bratati
  full_name: Kahali, Bratati
  last_name: Kahali
- first_name: Adam E
  full_name: Locke, Adam E
  last_name: Locke
- first_name: Tune H
  full_name: Pers, Tune H
  last_name: Pers
- first_name: Sailaja
  full_name: Vedantam, Sailaja
  last_name: Vedantam
- first_name: Andrew R
  full_name: Wood, Andrew R
  last_name: Wood
- first_name: Wouter
  full_name: van Rheenen, Wouter
  last_name: van Rheenen
- first_name: Ole A
  full_name: Andreassen, Ole A
  last_name: Andreassen
- first_name: Paolo
  full_name: Gasparini, Paolo
  last_name: Gasparini
- first_name: Andres
  full_name: Metspalu, Andres
  last_name: Metspalu
- first_name: Leonard H van den
  full_name: Berg, Leonard H van den
  last_name: Berg
- first_name: Jan H
  full_name: Veldink, Jan H
  last_name: Veldink
- first_name: Fernando
  full_name: Rivadeneira, Fernando
  last_name: Rivadeneira
- first_name: Thomas M
  full_name: Werge, Thomas M
  last_name: Werge
- first_name: Goncalo R
  full_name: Abecasis, Goncalo R
  last_name: Abecasis
- first_name: Dorret I
  full_name: Boomsma, Dorret I
  last_name: Boomsma
- first_name: Daniel I
  full_name: Chasman, Daniel I
  last_name: Chasman
- first_name: Eco J C
  full_name: de Geus, Eco J C
  last_name: de Geus
- first_name: Timothy M
  full_name: Frayling, Timothy M
  last_name: Frayling
- first_name: Joel N
  full_name: Hirschhorn, Joel N
  last_name: Hirschhorn
- first_name: Jouke Jan
  full_name: Hottenga, Jouke Jan
  last_name: Hottenga
- first_name: Erik
  full_name: Ingelsson, Erik
  last_name: Ingelsson
- first_name: Ruth J F
  full_name: Loos, Ruth J F
  last_name: Loos
- first_name: Patrik K E
  full_name: Magnusson, Patrik K E
  last_name: Magnusson
- first_name: Nicholas G
  full_name: Martin, Nicholas G
  last_name: Martin
- first_name: Grant W
  full_name: Montgomery, Grant W
  last_name: Montgomery
- first_name: Kari E
  full_name: North, Kari E
  last_name: North
- first_name: Nancy L
  full_name: Pedersen, Nancy L
  last_name: Pedersen
- first_name: Timothy D
  full_name: Spector, Timothy D
  last_name: Spector
- first_name: Elizabeth K
  full_name: Speliotes, Elizabeth K
  last_name: Speliotes
- first_name: Michael E
  full_name: Goddard, Michael E
  last_name: Goddard
- first_name: Jian
  full_name: Yang, Jian
  last_name: Yang
- first_name: Peter M
  full_name: Visscher, Peter M
  last_name: Visscher
citation:
  ama: Robinson MR, Hemani G, Medina-Gomez C, et al. Population genetic differentiation
    of height and body mass index across Europe. <i>Nature Genetics</i>. 2015;47(11):1357-1362.
    doi:<a href="https://doi.org/10.1038/ng.3401">10.1038/ng.3401</a>
  apa: Robinson, M. R., Hemani, G., Medina-Gomez, C., Mezzavilla, M., Esko, T., Shakhbazov,
    K., … Visscher, P. M. (2015). Population genetic differentiation of height and
    body mass index across Europe. <i>Nature Genetics</i>. Springer Nature. <a href="https://doi.org/10.1038/ng.3401">https://doi.org/10.1038/ng.3401</a>
  chicago: Robinson, Matthew Richard, Gibran Hemani, Carolina Medina-Gomez, Massimo
    Mezzavilla, Tonu Esko, Konstantin Shakhbazov, Joseph E Powell, et al. “Population
    Genetic Differentiation of Height and Body Mass Index across Europe.” <i>Nature
    Genetics</i>. Springer Nature, 2015. <a href="https://doi.org/10.1038/ng.3401">https://doi.org/10.1038/ng.3401</a>.
  ieee: M. R. Robinson <i>et al.</i>, “Population genetic differentiation of height
    and body mass index across Europe,” <i>Nature Genetics</i>, vol. 47, no. 11. Springer
    Nature, pp. 1357–1362, 2015.
  ista: Robinson MR, Hemani G, Medina-Gomez C, Mezzavilla M, Esko T, Shakhbazov K,
    Powell JE, Vinkhuyzen A, Berndt SI, Gustafsson S, Justice AE, Kahali B, Locke
    AE, Pers TH, Vedantam S, Wood AR, van Rheenen W, Andreassen OA, Gasparini P, Metspalu
    A, Berg LH van den, Veldink JH, Rivadeneira F, Werge TM, Abecasis GR, Boomsma
    DI, Chasman DI, de Geus EJC, Frayling TM, Hirschhorn JN, Hottenga JJ, Ingelsson
    E, Loos RJF, Magnusson PKE, Martin NG, Montgomery GW, North KE, Pedersen NL, Spector
    TD, Speliotes EK, Goddard ME, Yang J, Visscher PM. 2015. Population genetic differentiation
    of height and body mass index across Europe. Nature Genetics. 47(11), 1357–1362.
  mla: Robinson, Matthew Richard, et al. “Population Genetic Differentiation of Height
    and Body Mass Index across Europe.” <i>Nature Genetics</i>, vol. 47, no. 11, Springer
    Nature, 2015, pp. 1357–62, doi:<a href="https://doi.org/10.1038/ng.3401">10.1038/ng.3401</a>.
  short: M.R. Robinson, G. Hemani, C. Medina-Gomez, M. Mezzavilla, T. Esko, K. Shakhbazov,
    J.E. Powell, A. Vinkhuyzen, S.I. Berndt, S. Gustafsson, A.E. Justice, B. Kahali,
    A.E. Locke, T.H. Pers, S. Vedantam, A.R. Wood, W. van Rheenen, O.A. Andreassen,
    P. Gasparini, A. Metspalu, L.H. van den Berg, J.H. Veldink, F. Rivadeneira, T.M.
    Werge, G.R. Abecasis, D.I. Boomsma, D.I. Chasman, E.J.C. de Geus, T.M. Frayling,
    J.N. Hirschhorn, J.J. Hottenga, E. Ingelsson, R.J.F. Loos, P.K.E. Magnusson, N.G.
    Martin, G.W. Montgomery, K.E. North, N.L. Pedersen, T.D. Spector, E.K. Speliotes,
    M.E. Goddard, J. Yang, P.M. Visscher, Nature Genetics 47 (2015) 1357–1362.
date_created: 2020-04-30T10:58:23Z
date_published: 2015-09-14T00:00:00Z
date_updated: 2021-01-12T08:15:13Z
day: '14'
doi: 10.1038/ng.3401
extern: '1'
intvolume: '        47'
issue: '11'
language:
- iso: eng
month: '09'
oa_version: None
page: 1357-1362
publication: Nature Genetics
publication_identifier:
  issn:
  - 1061-4036
  - 1546-1718
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
status: public
title: Population genetic differentiation of height and body mass index across Europe
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 47
year: '2015'
...