Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Pirro G. Hysi; Ana M. Valdes; Fan Liu; Nicholas A. Furlotte; David M. Evans; Veronique Bataille; Alessia Visconti; Gibran Hemani; George McMahon; Susan M. Ring; George Davey Smith; David L. Duffy; Gu Zhu; Scott D. Gordon; Sarah E. Medland; Bochao D. Lin; Gonneke Willemsen; Jouke Jan Hottenga; Dragana Vuckovic; Giorgia Girotto; Ilaria Gandin; Cinzia Sala; Maria Pina Concas; Marco Brumat; Paolo Gasparini; Daniela Toniolo; Massimiliano Cocca; Antonietta Robino; Seyhan Yazar; Alex W. Hewitt; Yan Chen; Changqing Zeng; Andre G. Uitterlinden; M. Arfan Ikram; Merel A. Hamer; Cornelia M. Van Duijn; Tamar Nijsten; David A. MacKey; Mario Falchi; Dorret I. Boomsma; Nicholas G. Martin; David A. Hinds; Manfred Kayser; Timothy D. Spector

doi:10.1038/s41588-018-0100-5

Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Pirro G. Hysi, Ana M. Valdes, Fan Liu, Nicholas A. Furlotte, David M. Evans, Veronique Bataille, Alessia Visconti, Gibran Hemani, George McMahon, Susan M. Ring, George Davey Smith, David L. Duffy, Gu Zhu, Scott D. Gordon, Sarah E. Medland, Bochao D. Lin, Gonneke Willemsen, Jouke Jan Hottenga, Dragana Vuckovic, Giorgia GirottoIlaria Gandin, Cinzia Sala, Maria Pina Concas, Marco Brumat, Paolo Gasparini, Daniela Toniolo, Massimiliano Cocca, Antonietta Robino, Seyhan Yazar, Alex W. Hewitt, Yan Chen, Changqing Zeng, Andre G. Uitterlinden, M. Arfan Ikram, Merel A. Hamer, Cornelia M. Van Duijn, Tamar Nijsten, David A. MacKey, Mario Falchi, Dorret I. Boomsma, Nicholas G. Martin, David A. Hinds, Manfred Kayser^*, Timothy D. Spector

^*Corresponding author for this work

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Abstract

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

Original language	English
Pages (from-to)	652-656
Number of pages	5
Journal	Nature Genetics
Volume	50
Issue number	5
Early online date	16 Apr 2018
DOIs	https://doi.org/10.1038/s41588-018-0100-5
Publication status	Published - May 2018

Funding

The INGI research was supported by funds from Compagnia di San Paolo, Torino, Italy; Fondazione Cariplo, Italy and Ministry of Health, Ricerca Finalizzata 2008 and CCM 2010 and Telethon, Italy. Additional support was provided by the Italian Ministry of Health (RF 2010 to PG), FVG Region, and Fondo Trieste. The NTR study was supported by multiple grants from the Netherlands Organization for Scientific Research (NWO: 016-115-035, 463-06-001, 451-04-034), ZonMW (31160008, 911-09-032); from the Institute for Health and Care Research (EMGO+); and from the Biomolecular Resources Research Infrastructure (BBMRI-NL, 184.021.007), European Research Council (ERC-230374). Genotyping was made possible by grants from NWO/SPI 56-464-14192, Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health, Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls (USA), and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). B.D.L. is supported by a PhD grant (201206180099) from the China Scholarship Council. QIMR funding was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498), the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), and the US National Institutes of Health (NIH grants AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206). Statistical analyses were carried out on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). S.E.M. and D.L.D. are supported by the National Health and Medical Research Council (NHMRC) Fellowship Scheme. The 20-year follow-up of Generation 2 of the Western Australian Pregnancy Cohort (Raine) Study was funded by Australian National Health and Medical Research Council (NHMRC) project grant 1021105, Lions Eye Institute, the Australian Foundation for the Prevention of Blindness, and the Ophthalmic Research Institute of Australia. S.Y. is supported by NHMRC Early Career Fellowship (CJ Martin - Overseas Biomedical Fellowship). The Rotterdam Study is supported by the Netherlands Organization of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is supported by the Erasmus MC and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE) the Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sport; the European Commission (DG XII); and the Municipality of Rotterdam. The generation and management of GWAS genotype data for the Rotterdam Study were executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC. F.L. is supported by a Chinese recruiting program, the National Thousand Young Talents Award, and by the National Natural Science Foundation of China (NSFC) (91651507). This research has been conducted using the UK Biobank Resource under Application Number 12052. The ALSPAC work is supported by a Medical Research Council program grant (MC_UU_12013/4 to D.M.E). The UK Medical Research Council and the Wellcome Trust (grant refs: 092731 and 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. D.M.E. is supported by an Australian Research Council Future Fellowship (FT130101709). This publication is the work of the authors and D.M.E. will serve as guarantor for the contents of this paper. ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The ERF Study was supported by the joint grant from the Netherlands Organization for Scientific Research (NWO, 91203014), the Center of Medical Systems Biology (CMSB), Hersenstichting Nederland, Internationale Stichting Alzheimer Onderzoek (ISAO), Alzheimer Association project number 04516, Hersenstichting Nederland project number 12F04(2).76, and the Interuniversity Attraction Poles (IUAP) program. As a part of EUROSPAN (European Special Populations Research Network), ERF was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the program “Quality of Life and Management of the Living Resources” of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by joint grant from Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). The TwinsUK study was funded by the Wellcome Trust (105022/Z/14/Z); European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas’ NHS Foundation Trust in partnership with King's College London. SNP genotyping was performed by the Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR.

Funders	Funder number
Alzheimer Association	12F04(2).76, 04516
Australian Foundation for the Prevention of Blindness
Australian National Health and Medical Research Council	442981, 552498, 496739, 389875, 339462, 389892, 389891, 442915, 241944, 552485, 389927, 389938
Avera Institute
BBMRI-NL	184.021.007
Biomolecular Resources Research Infrastructure
Center of Medical Systems Biology
European Commission FP6 STRP	018947, LSHG-CT-2006-01947
European Special Populations Research Network
FP-5 GenomEUtwin Project	QLG2-CT-2002-01254
FP7/2007	HEALTH-F4-2007-201413
Institute for Health and Care Research
Interuniversity Attraction Poles
Italian Ministry of Health	RF 2010
Lions Eye Institute
Ministry of Education, Culture and Science
NWO-RFBR	047.017.043
Netherlands Genomics Initiative
Netherlands Organization for Health Research and Development
Netherlands Organization for Scientific Research	016-115-035, 463-06-001, 451-04-034
Netherlands Organization of Scientific Research NWO
Netherlands Scientific Organization
Quality of Life and Management of the Living Resources” of 5th Framework Programme
RIDE2
Research Institute for Diseases in the Elderly	014-93-015
US National Institutes of Health
National Institutes of Health	1RC2 MH089951, 1RC2 MH089995, MH081802, 201206180099, R01 HD042157-01A1
National Institute of Mental Health	U24 MH068457-06
National Institute on Alcohol Abuse and Alcoholism	R01AA013321
Sioux Falls Area Community Foundation
Compagnia di San Paolo
Wellcome Trust	105022/Z/14/Z, 102215/2/13/2, 092731
Medical Research Council	MC_UU_12013/4
National Institute for Health Research
European Commission
European Research Council	ERC-230374, NWO/SPI 56-464-14192
University of Bristol
Australian Research Council	A7960034, DP0212016, FT130101709, A79801419, DP0343921, A79906588, DP0770096
National Health and Medical Research Council	1021105
Ophthalmic Research Institute of Australia
National Natural Science Foundation of China	91651507
ZonMw	31160008, 911-09-032
Erasmus Universiteit Rotterdam
Russian Foundation for Basic Research
Fondazione Telethon
Fondazione Cariplo
Ministerie van Volksgezondheid, Welzijn en Sport
Erasmus Medisch Centrum
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	480-05-003, 91203014
China Scholarship Council
Seventh Framework Programme
Ministeriet Sundhed Forebyggelse
Hersenstichting
Internationale Stichting Alzheimer Onderzoek

Keywords

Journal Article

Cohort Studies

Netherlands Twin Register (NTR)

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10.1038/s41588-018-0100-5

Genome-wide association metaanalysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritabilityFinal published version, 1.75 MBLicence: Article 25fa Dutch Copyright Act

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Hysi, P. G., Valdes, A. M., Liu, F., Furlotte, N. A., Evans, D. M., Bataille, V., Visconti, A., Hemani, G., McMahon, G., Ring, S. M., Smith, G. D., Duffy, D. L., Zhu, G., Gordon, S. D., Medland, S. E., Lin, B. D., Willemsen, G., Hottenga, J. J., Vuckovic, D., ... Spector, T. D. (2018). Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability. Nature Genetics, 50(5), 652-656. https://doi.org/10.1038/s41588-018-0100-5

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abstract = "Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6\% of red hair, 24.8\% of blond hair, and 26.1\% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.",

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author = "Hysi, \{Pirro G.\} and Valdes, \{Ana M.\} and Fan Liu and Furlotte, \{Nicholas A.\} and Evans, \{David M.\} and Veronique Bataille and Alessia Visconti and Gibran Hemani and George McMahon and Ring, \{Susan M.\} and Smith, \{George Davey\} and Duffy, \{David L.\} and Gu Zhu and Gordon, \{Scott D.\} and Medland, \{Sarah E.\} and Lin, \{Bochao D.\} and Gonneke Willemsen and Hottenga, \{Jouke Jan\} and Dragana Vuckovic and Giorgia Girotto and Ilaria Gandin and Cinzia Sala and Concas, \{Maria Pina\} and Marco Brumat and Paolo Gasparini and Daniela Toniolo and Massimiliano Cocca and Antonietta Robino and Seyhan Yazar and Hewitt, \{Alex W.\} and Yan Chen and Changqing Zeng and Uitterlinden, \{Andre G.\} and Ikram, \{M. Arfan\} and Hamer, \{Merel A.\} and \{Van Duijn\}, \{Cornelia M.\} and Tamar Nijsten and MacKey, \{David A.\} and Mario Falchi and Boomsma, \{Dorret I.\} and Martin, \{Nicholas G.\} and Hinds, \{David A.\} and Manfred Kayser and Spector, \{Timothy D.\}",

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Hysi, PG, Valdes, AM, Liu, F, Furlotte, NA, Evans, DM, Bataille, V, Visconti, A, Hemani, G, McMahon, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Lin, BD, Willemsen, G, Hottenga, JJ, Vuckovic, D, Girotto, G, Gandin, I, Sala, C, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, AW, Chen, Y, Zeng, C, Uitterlinden, AG, Ikram, MA, Hamer, MA, Van Duijn, CM, Nijsten, T, MacKey, DA, Falchi, M, Boomsma, DI, Martin, NG, Hinds, DA, Kayser, M & Spector, TD 2018, 'Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability', Nature Genetics, vol. 50, no. 5, pp. 652-656. https://doi.org/10.1038/s41588-018-0100-5

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AB - Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

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JF - Nature Genetics

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ER -

Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

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