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Meta-analysis of GWA studies provides new insights on the genetic architecture of skin pigmentation in recently admixed populations.pdf (934.41 kB)

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

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posted on 2019-08-09, 09:15 authored by F Lona-Durazo, N Hernandez-Pacheco, S Fan, T Zhang, J Choi, MA Kovacs, SK Loftus, P Le, M Edwards, CA Fortes-Lima, C Eng, S Huntsman, D Hu, EJ Gómez-Cabezas, LC Marín-Padrón, J Grauholm, O Mors, EG Burchard, HL Norton, WJ Pavan, KM Brown, S Tishkoff, M Pino-Yanes, S Beleza, B Marcheco-Teruel, EJ Parra
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: Our meta-analysis of skin pigmentation GWAS in recently admixed populations provides new insights about the genetic architecture of this complex trait.


The genotyping of the Cuban sample was supported by the Ministry of Public Health, Cuba, and The Cuban-Danish collaborating project on Case-Controls Study for Bipolar Disorder and Schizophrenia. EJP received funding from the Natural Sciences and Engineering Research Council of Canada (NSERC Discovery Grant). Computations were performed on the GPC supercomputer at the SciNet HPC Consortium, Canada. SciNet is funded by: the Canada Foundation for Innovation under the auspices of Compute Canada; the Government of Ontario; Ontario Research Fund-Research Excellence; and the University of Toronto. FLD is supported by the National Council for Science and Technology (CONACYT) in Mexico. SB is currently supported by the Medical Research Council (grant number MR/M01987X/1). NH-P was funded by a fellowship (grant number FI16/00136) from the Instituto de Salud Carlos III (ISCIII) (NH-P) and co-funded by the European Social Funds from the European Union (ESF) “ESF invests in your future”. MP-Y was funded by the Ramón y Cajal Program (fellowship number RYC-2015-17205) by the Spanish Ministry of Economy, Industry and Competitiveness, and by ISCIII through AES and EC within AAL framework and the SysPharmPedia (award number AC15/00015), awarded from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020. ST was supported by National Institutes of Health (grant numbers 1R01DK104339–0, 1R01GM113657–01) and the National Science Foundation (grant number BCS-1317217). EGB was funded by the Sandler Family Foundation; the American Asthma Foundation; the Robert Wood Johnson Foundation Amos Medical Faculty Development Program; Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II; National Institutes of Health (grant numbers 1R01HL117004, R01Hl128439); National Institute of Health and Environmental Health Sciences (grant numbers R01ES015794, R21ES24844); the National Institute on Minority Health and Health Disparities (



BMC Genetics, 2019, 20, Article number: 59

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We provide the list of all genome-wide (p < 5 × 10^− 8) and suggestive (p < 10^− 5) signals identified in the meta-analysis as a supplementary information file (Additional file 3). The complete summary data of the meta-analysis is available from the corresponding author upon request.



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