The human eye color is a quantitative trait displaying multifactorial inheritance. Several studies have shown that the OCA2 locus is the major contributor to the human eye color variation. By linkage analysis of a large Danish family, we finemapped the blue eye color locus to a 166 Kbp region within the HERC2 gene. By association analyses, we identified two SNPs within this region that were perfectly associated with the blue and brown eye colors: rs12913832 and rs1129038. Of these, rs12913832 is located 21.152 bp upstream from the OCA2 promoter in a highly conserved sequence in intron 86 of HERC2. The brown eye color allele of rs12913832 is highly conserved throughout a number of species. As shown by a Luciferase assays in cell cultures, the element significantly reduces the activity of the OCA2 promoter and electrophoretic mobility shift assays demonstrate that the two alleles bind different subsets of nuclear extracts. One single haplotype, represented by six polymorphic SNPs covering half of the 3' end of the HERC2 gene, was found in 155 blue-eyed individuals from Denmark, and in 5 and 2 blue-eyed individuals from Turkey and Jordan, respectively. Hence, our data suggest a common founder mutation in an OCA2 inhibiting regulatory element as the cause of blue eye color in humans. In addition, an LOD score of Z = 4.21 between hair color and D14S72 was obtained in the large family, indicating that RABGGTA is a candidate gene for hair color.

The role of the mitochondria in disease, general health and aging has drawn much attention over the years. Several attemptshave been made to describe how the numbersof mitochondriacorrelate with age, although with inconclusive results. In this study, the relativequantity of mitochondrial DNA compared to nuclear DNA,i.e. the mitochondrial DNA copy number, was measured by PCR technology and used as a proxy for the content of mitochondria copies. In 1,067 Danish twins and singletons (18-93 years of age), with the majority being elderly individuals, theestimated mean mitochondrial DNA copy numberin peripheral blood cells was similar for those 18-48 years of age (mean relative mtDNA content: 61.0; 95% CI [52.1; 69.9]), but declinedby −0.54 mtDNA 95%CI [−0.63; −0.45] every year for those older thanapproximately 50 years of age.However, the longitudinal, yearly decline within an individual was more than twice as steep as observed in the cross-sectional analysis (decline of mtDNA content: −1.27; 95%CI [−1.71; −0.82]). Subjects with low mitochondrial DNA copy numberhad poorer outcomes in terms of cognitive performance, physical strength, self-rated health, andhigher all-cause mortality than subjects with high mitochondrial DNA copy number, also when age was controlled for.The copy numbermortality associationcan contribute to the smaller decline in a cross-sectional sample of the population compared to the individual,longitudinal decline. This study suggests that high mitochondrial DNA copy number in blood is associated with betterhealth and survival among elderly.

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

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