Genetic Determinants of Skin Color, Aging, and Cancer

Chapter 1 gives a general introduction to this thesis. In Chapter 2 we validated perceived skin color as skin color measurement. In Chapter 3 we investigated whether digitally quantified skin color was a suitable measure to discover new skin color genes. In Chapter 4 we investigated the genetic basis of skin color by a genome-wide association study followed by a replication analysis in 17,262 individuals of European ancestry from the Netherlands, UK and Australia. In Chapter 5 we validated a new digital image analysis technique to measure severity of different skin aging features including wrinkling, pigmented spots and telangiectasia. In Chapter 6 we have used the digitally quantified pigmented spots measures to search for associated genetic variants. In Chapter 7 we studied intrinsic and extrinsic risk factors for the skin aging feature sagging eyelids. In Chapter 8 we investigated genetic susceptibility to the pre-malignant actinic keratosis. In Chapter 9 we have summarized the pattern of genetic association between 13 genes and pigmentation traits, pigmented spots, and cutaneous malignancies. In Chapter 10 we discuss the results of all studies in this thesis

Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up

In the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations

Commentary on: “A genome-wide association study in Caucasian women suggests the involvement of HLA genes in the severity of facial solar lentigines” by Laville et al., 2016

We have read with interest the study by Laville et al. that was published in the September 2016 issue of PCMR (Laville et al., 2016) and that represents the second genome-wide association study of facial solar lentigines. This study (SU.VI.MAX cohort) showed two novel genetic regions, both located on chromosome 6 [6p22 intergenic region (p = 1.6 9 10 -6) and 6p21 USP81P/HLA-C region (p = 2.5 9 10 -7)] but both not significantly associated with solar lentigines based on the genome-wide association study. Laville et al. reported, however, that one SNP in the 6p22 region was significantly associated with forehead lentigines in a recessive model (p = 1.4 9 10 -8). We were interested in the question of whether we could replicate these findings in our cohort of 2844 Dutch North Europeans (mean age 67 years, 53% women). This is a subgroup of the Rotterdam Study (RS), for whom facial pigmented spots (mainly solar lentigines) were quantified as the percentage of affected skin area using digital facial photographs (Jacobs et al., 2015). We tried to select Laville et al. top SNPs in our data. From the 6p22 region, the two top SNPs of Laville were available in the RS as imputed SNPs. These two SNPs were both not associated with pigmented spots in our data (rs9350204: p = 0.62 and rs9358294: p = 0.60). From the 6p21 region, none of the top SNPs (rs2853949, rs2844614, rs2844613, rs2524069, rs2853947, rs2524067, and rs2524065) reported by Laville were available in our data. We tried to identify SNPs that were in linkage disequilibrium (LD) with the SNPs reported by Laville et al. using data from the 1000 Genomes Browser. Using the latest genome build, we noted that the SNPs map ambiguously to different regions of the genome (for example: http://www. ensembl.org/Homo_sapiens/Variation/Explore?db=core;v= rs2853949;vdb=variation). Using the previous genome build (GRCh37), we downloaded pair-wise LD (R2), encompassing the region 6:31233540-631253539 that included the SNPs the authors reported, and we looked into the RS for associations. Of these, 39 SNPs were available in the RS database (Table S1). None of the SNPs were significantly associated with pigmented spots (p > 0.30), although the R2 indicating LD with rs2853949 for the 39 SNPs is poor to moderate (<0.36), or unknown (ST1). It should be noted that the region reported by Laville et al. is located at the major histocompatibility complex (MHC), which is one of the most variable regions in the human genome (De Bakker and Raychaudhuri, 2012; Traherne et al., 2006). Within the HLA, the regions of LD are large due to a low recombination rate and adaptive selection (Gourraud et al., 2014). Therefore, associations in these regions should be taken with caution, as mapping SNPs to these regions is problematic. The Rotterdam Study cohort and the SU.VI.MAX cohort are somewhat different. SU.VI.MAX consists solely of young women (mean age 53 years), and solar lentigines were manually graded using a photographic scale. The genetic analysis in the Rotterdam Study was adjusted for skin color and in SU.VI.MAX for cumulative sun exposure. However, we do not think that these minor differences account for the complete lack of replication. More likely, the size of the discovery cohort (n = 500) is too small to detect a true positive finding (Ioannidis et al., 2009). As they describe in their article, their power to detect a SNP with an explained variance of 5% is only 35%. This power is even lower, because 5% explained variance is unrealistically high (Mccarthy et al., 2008). The low power is also illustrated by the fact that Laville et al. replicated the association between solar lentigines and the rs12203592 in IRF4 (Jacobs et al., 2015) with a p-value of only 0.01, whereas the p-value in the RS was 10 -27. The finding of HLA-C (an immunity related gene) is an appealing finding, because immunity could well play an important role in the origin of solar lentigines. Nevertheless, this finding should be first confirmed by additional studies. Therefore, we advocate for replication of genome-wide association study findings whenever possible