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- W2936777995 abstract "Research into the genetic architecture of chronic disease has unequivocally demonstrated etiological contributions from both common (polymorphisms; SNPs) and rare (mutations) genetic variants. For alopecia areata, our GWAS successfully identified SNPs that increase disease risk, however, mutations remain to be identified. While exome sequencing permits genome-wide investigation of disease mutations, challenges arise because human genomes are riddled with mutations, most of which exert no effect on health, and because low allele frequencies limit power to detect associations. Therefore, new methods are needed to identify causal mutations in chronic disease. Here, we developed a novel analytic pipeline to identify mutations that contribute to alopecia areata etiology. First, genome-wide tagSNPs were used to perform linkage analysis and family-based association tests, which identified 20 cosegregating regions (4>LOD>1) that contain 373 associated tagSNPs, capturing variation in 6,688 SNPs and implicating 178 genes. Next, we performed exome sequencing on a subset of probands and extracted co-segregating mutations that alter protein sequence in these 178 genes, reducing the number of candidate genes to 58. Pathway analysis of these 58 genes indicated that 12 genes from 5 genomic regions contribute to extracellular matrix (ECM) structure, organization and/or signaling (0.016<p<9x10-4). Replication analyses are underway in a set of 124 patients with family history and 651 patients who did not report family history. Because the physical and biochemical properties of ECM can regulate CD4+ and CD8+ T-cell responses, our results uncover a new biological point of intervention for inhibiting aberrant immune-mediated destruction of the hair follicle." @default.
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- W2936777995 date "2019-05-01" @default.
- W2936777995 modified "2023-09-26" @default.
- W2936777995 title "393 Rare genetic mutations identify extracellular matrix genes as a contributing factor in alopecia areata etiology" @default.
- W2936777995 doi "https://doi.org/10.1016/j.jid.2019.03.469" @default.
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