Genetic studies of vitiligo

描述（由申请人提供）：这是一份重新提交的续期申请，以继续进行全身性白癜风（GV）的遗传研究，GV是一种常见的自身免疫性疾病，其中皮肤和头发的白色斑块是由黑素细胞破坏引起的。GV中显著的皮肤色素沉着尤其影响有色人种，经常出现社会孤立和精神合并症。此外，GV患者有~30%的风险发生其他自身免疫性疾病，导致直接的医疗合并症。我们的GV遗传研究始于15年前的遗传和临床流行病学基础研究，随后是候选基因关联研究和全基因组连锁研究。在过去的资助期间，我们组织了国际葡萄基因联盟，在欧洲来源的白人（EUR）中进行了两次非常成功的GWAS，以及对其他人群的研究，确定了约32个GV易感基因并定义了新的病理生物学途径。除了GWAS之外，我们还对第一次GWAS检测到的大多数基因进行了NextGen重测序，确定了HLA-A、TYR、NLRP1和GZMB中常见的（和一些不常见/罕见的）因果变异。到目前为止确定的潜在因果变异，以及本提案中确定的变异，将在我们的平行项目“白癜风基因的功能分析”（AR045584）中进行功能分析。我们的研究结果

DESCRIPTION (provided by applicant): This is a resubmitted renewal proposal to continue genetic studies of generalized vitiligo (GV), a common autoimmune disease in which white patches of skin and hair result from destruction of melanocytes. Striking skin depigmentation in GV particularly impacts persons of color, with frequent social isolation and psychiatric co- morbidity. In addition, GV patients have ~30% risk of developing other autoimmune diseases, resulting in direct medical co-morbidity. Our genetic studies of GV began 15 years ago with basic studies of genetic and clinical epidemiology, followed by candidate gene association studies and genomewide linkage studies. During the past grant period we organized the International VitGene Consortium to perform two highly successful GWAS in European-derived whites (EUR), as well as studies of other populations, identifying ~32 GV susceptibility genes and defining novel pathobiological pathways. Beyond the GWAS, we have gone on to NextGen re-sequencing of most of the genes detected by the first GWAS, identifying common (and some uncommon/rare) causal variants in HLA-A, TYR, NLRP1, and GZMB. Potential causal variants identified in to date, as well as those identified in this proposal, are carried forward to functioal analysis in our parallel project, "Functional Analysis of Vitiligo Genes" (AR045584). Our findings provide the basis of the first theoretical biological framework for vitiligo autoimmune pathogenesis, and have translated directly to improved patient classification and improved treatment. Nevertheless, known GV loci account for only ~18% of GV heritability (h2), and most causal gene variants remain unknown. Statistical genetic analysis of our combined GV GWAS datasets shows that considerable "hidden" h2 for GV resides in the remaining data, which can be mined at relatively low cost. Our goals are thus to augment the GV "parts list" of genes and pathways, identify causal variants, relate GV genetic and allelic architecture to clinical sub-phenotypes and disease biomarkers, and understand causal functional biology. A strong rationale to discover additional GV loci is that we do not yet know enough biology to control melanocyte-directed autoimmunity. If this could be achieved, GV would be one of the best AI disease candidates for regenerative medicine, since the skin melanocyte (or melanocyte stem cell) reservoir remains intact. Here, we thus propose to: 1) carry out a small third EUR GWAS to mine additional GV loci, powered to OR ~1.2 (probably the practical limit of GWAS); 2) fine-map GV loci to identify specific genes and define common and some uncommon causal variants; followed by two innovative Aims, to 3) identify potential uncommon/rare causal variants by analyses of multiplex GV families; and 4) relate the genetic architecture of GV to specific clinical and biomarker sub-phenotypes and test whether the same GV loci/variants also cause a related phenotype, segmental vitiligo (SV). It is our goal that the resultant biological knowledge will provide the basis for new approaches to treatment and even prevention of GV and associated autoimmune diseases.