Expanded Analysis of Pigmentation Genetics in UK Biobank
Expanded Analysis of Pigmentation Genetics in UK Biobank
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DOI：
10.1101/2022.01.30.478418
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发表时间：
2022-01
期刊：
影响因子：
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通讯作者：
E. Pairo-Castineira;Jaime Cornelissen;K. Rawlik;O. Canela‐Xandri;S. Loftus;W. Pavan;K. Brown;A. Tenesa;I. Jackson
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文献类型：
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作者：
E. Pairo-Castineira;Jaime Cornelissen;K. Rawlik;O. Canela‐Xandri;S. Loftus;W. Pavan;K. Brown;A. Tenesa;I. Jackson
色素沉着的遗传学是一个很好的模型，可以用来理解几乎完全不受环境影响的性状中的基因相互作用。我们使用DISSECT分析了英国生物库中的色素沉着表型，DISSECT是一种能够进行全基因组关联研究（GWAS）的工具，同时考虑了个体之间的相关性，因此可以研究更大的队列。我们已经增加了与红色和金色头发颜色、基础肤色和对紫外线辐射的晒黑反应相关的候选基因的数量。如前所述，我们发现几乎所有的红发个体都有两个变异的MC 1 R等位基因;外显子组序列数据扩大了相关编码变体的数量。只有一个单一的MC 1 R变异的罕见的红头发的个人富集在ASIP基因的相关的eQTL。我们发现，女性最有可能自我报告红色或金色的头发，苍白的皮肤和晒黑能力低于男性，并且KITLG，MC 1 R，OCA 2和IRF 4的变体显示出显着的性别差异。在考虑性别因素后，色素沉着表型与性激素水平无关，除了晒黑能力，这与男性的睾酮呈正相关。在英国各地，出生地和头发颜色之间存在相关性;红色头发在北部和西部更常见，而金色头发在东部更常见。将GWAS与转录组数据相结合以产生转录组范围关联研究，从而鉴定其在皮肤或黑素细胞中的表达显示与色素沉着表型相关的候选基因。与不同色素沉着表型相关的候选人的比较发现，金发而不是肤色的候选人富含皮肤和头发基因，这表明可能是头发形状和结构影响头发颜色，而不是黑素细胞/角质形成细胞的相互作用。
The genetics of pigmentation is an excellent model for understanding gene interactions in a trait almost entirely unaffected by environment. We have analysed pigmentation phenotypes in UK Biobank using DISSECT, a tool which enables genome-wide association studies (GWAS) whilst accounting for relatedness between individuals, and thus allows a much larger cohort to be studied. We have increased the number of candidate genes associated with red and blonde hair colour, basal skin colour and tanning response to UV radiation. As previously described, we find almost all red hair individuals have two variant MC1R alleles; exome sequence data expands the number of associated coding variants. Rare red-headed individuals with only a single MC1R variant are enriched for an associated eQTL at the ASIP gene. We find that females are most likely to self-report red or blonde hair, paler skin and less tanning ability than men, and that variants at KITLG, MC1R, OCA2 and IRF4 show significant sex differences in effect. After taking sex into account, pigmentation phenotypes are not correlated with sex hormone levels, except for tanning ability, which shows a positive correlation with testosterone in men. Across the UK there is a correlation between place of birth and hair colour; red hair being more common in the north and west, whilst blonde hair is more common in the east. Combining GWAS with transcriptome data to generate a transcriptome wide association study identifies candidate genes whose expression in skin or melanocytes shows association with pigmentation phenotypes. A comparison of candidates associated with different pigmentation phenotypes finds that candidates for blonde hair, but not skin colour, are enriched for skin and hair genes suggesting that it may be hair shape and structure that impacts hair colour, rather than the melanocyte/keratinocyte interaction.