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Pemphigus is an autoimmune blistering disease, and pemphigus vulgaris (PV) and foliaceus (PF) are the two major histological subtypes. The associations of HLA molecules have been suggested, but specific HLA risk variants as well as novel risk variants outside the MHC region remain to be discovered. We performed a two-stage genome-wide association study of pemphigus in the Chinese Han population in 166 patients and 844 healthy controls with a follow-up analysis in an additional 105 patients and 996 healthy controls. Further, a comprehensive association analysis of the MHC region was performed by HLA imputation and further validation by next-generation sequencing and genotyping. Novel associations with PF were discovered SNP on 12q24.33, located within RAN and STX2 (P PF ¼1.57Â10-9).. In addition, HLA-DRB1*14 has been demonstrated to be the primary driver of HLA association for both PV (P¼1.39Â10-85) and PF (P¼1.69Â10-19), but the association patterns of DRB1*14 alleles are different between two subtypes. Discovery of these risk loci has advanced our understanding of the genetic basis of pemphigus susceptibility, and offered opportunities for risk prediction and preventive treatment for pemphigus, in particular for PV.

SASH1 has recently been identified as a novel pigmentation gene. Mutations in SASH1 cause inherited pigmentation disorders including lentigines, a common form of hyperpigmentation in human skin. Studying the function of SASH1 and associated disorders will likely lead to new insight to melanocyte biology and pathological mechanisms for pigmentation disorders. Many inherited lentigines have increased melanocyte proliferation through activation of the RAS/RAF/MAPK signaling. Our histological examination of skin biopsies from SASH1 mutation affected individuals showed increased numbers of melanocytes; however, no obvious increases in proliferating melanocytes were observed. Melanocyte-derived cell culture transfection and stable transduction showed that overexpressing wild type of mutated SASH1 did not alter MAPK signaling and the mutation in SASH1 did not increase proliferation or survival. Conversely, knockdown of SASH1 in melanocyte-lineage cells altered cell morphology and induced pigmentation production, consistent with more differentiated status. Furthermore, clinical examination identified that affected individuals displayed premature hair graying as young adults, strongly supporting aberrant differentiation as a pathological mechanism. To characterize the molecular mechanisms better, we are currently using multiple patient-specific iPSC clones and functional melanocytes from two affected individuals, and multiple gene-corrected isogenic iPSC clones. In sum, we identified hair graying as a new phenotype associated with SASH1-mediated disorders and aberrant differentiation of melanocyte lineage as a potential new mechanism for pigmentation disorders.