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BMC Genet. 2019 Jul 17;20(1):59. doi: 10.1186/s12863-019-0765-5.

Meta-analysis of GWA studies provides new insights on the genetic architecture of skin pigmentation in recently admixed populations.

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Department of Anthropology, University of Toronto at Mississauga, Health Sciences Complex, room 352, Mississauga, Ontario, L5L 1C6, Canada.
Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.
Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna, Tenerife, Spain.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, USA.
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, USA.
Evolutionary Anthropology Team, Laboratory Eco-Anthropology and Ethno-Biology UMR7206, CNRS-MNHN-University Paris Diderot, Musée de l'Homme, Paris, France.
Department of Organismal Biology, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden.
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
Centre for Sociological and Psychological Research, Havana, Cuba.
National Centre of Medical Genetics, Medical University of Havana, La Habana, Cuba.
Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus University, Aarhus, Denmark.
Psychiatric Department, Aarhus University Hospital, Aarhus, Denmark.
Department of Anthropology, University of Cincinnati, Cincinnati, USA.
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, Santa Cruz de Tenerife, Spain.
Department of Genetics and Genome Biology, College of Life Sciences, University of Leicester, Leicester, UK.
Department of Anthropology, University of Toronto at Mississauga, Health Sciences Complex, room 352, Mississauga, Ontario, L5L 1C6, Canada.



Association studies in recently admixed populations are extremely useful to identify the genetic architecture of pigmentation, due to their high genotypic and phenotypic variation. However, to date only four Genome-Wide Association Studies (GWAS) have been carried out in these populations.


We present a GWAS of skin pigmentation in an admixed sample from Cuba (N = 762). Additionally, we conducted a meta-analysis including the Cuban sample, and admixed samples from Cape Verde, Puerto Rico and African-Americans from San Francisco. This meta-analysis is one of the largest efforts so far to characterize the genetic basis of skin pigmentation in admixed populations (N = 2,104). We identified five genome-wide significant regions in the meta-analysis, and explored if the markers observed in these regions are associated with the expression of relevant pigmentary genes in human melanocyte cultures. In three of the regions identified in the meta-analysis (SLC24A5, SLC45A2, and GRM5/TYR), the association seems to be driven by non-synonymous variants (rs1426654, rs16891982, and rs1042602, respectively). The rs16891982 polymorphism is strongly associated with the expression of the SLC45A2 gene. In the GRM5/TYR region, in addition to the rs1042602 non-synonymous SNP located on the TYR gene, variants located in the nearby GRM5 gene have an independent effect on pigmentation, possibly through regulation of gene expression of the TYR gene. We also replicated an association recently described near the MFSD12 gene on chromosome 19 (lead variant rs112332856). Additionally, our analyses support the presence of multiple signals in the OCA2/HERC2/APBA2 region on chromosome 15. A clear causal candidate is the HERC2 intronic variant rs12913832, which has a profound influence on OCA2 expression. This variant has pleiotropic effects on eye, hair, and skin pigmentation. However, conditional and haplotype-based analyses indicate the presence of other variants with independent effects on melanin levels in OCA2 and APBA2. Finally, a follow-up of genome-wide signals identified in a recent GWAS for tanning response indicates that there is a substantial overlap in the genetic factors influencing skin pigmentation and tanning response.


Our meta-analysis of skin pigmentation GWAS in recently admixed populations provides new insights about the genetic architecture of this complex trait.


Admixed populations; Complex trait; Gene expression; Genome-wide association study; Haplotype; Meta-analysis; Skin pigmentation

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