Chao Zhang

BACKGROUND: The coronary microvasculature is crucial for proper cardiac function, and coronary microvascular disease (CMVD) has emerged as an underdiagnosed and undertreated cause of ischemic heart disease. FOG2 (friend of GATA 2) is a transcriptional co-regulator crucial for coronary development and the maintenance of the coronary microvasculature in adult mice. Little is known about the role of FOG2 in humans or its role in CMVD. Here, we report a genotype-first approach to determine the role of FOG2 in human CMVD. METHODS: We performed phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants. We interrogated MagNET heart tissue data to identify genes and pathways associated with rs28374544. We then overexpressed FOG2S657G in a cardiomyocyte cell line and assessed the effects on cardiac metabolism and paracrine angiogenic signaling. RESULTS: We identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Using phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants, we identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Individuals carrying the S657G variant, almost all of African ancestry, had increased chest pain, a smaller burden of obstructive coronary artery disease, and altered coronary blood flow. Differential gene and pathway analysis using several genomic data sets showed that carriers of S657G have increased expression of genes involved in angiogenesis, glycolysis, and the HIF (hypoxia-inducible factor) pathway. In vitro functional studies show that compared with the FOG2 wild-type protein, the FOG2 ^S657G variant protein promotes angiogenic gene expression and angiogenesis while decreasing oxygen consumption rate. CONCLUSIONS: A common functional coding variant in FOG2, S657G, is associated with CMVD in humans. Altered angiogenic gene expression, regulated in part by FOG2, may contribute to CMVD.

Using genome-wide data of 89 ancient individuals dated to 5100 to 100 years before the present (B.P.) from 29 sites across the Tibetan Plateau, we found plateau-specific ancestry across plateau populations, with substantial genetic structure indicating high differentiation before 2500 B.P. Northeastern plateau populations rapidly showed admixture associated with millet farmers by 4700 B.P. in the Gonghe Basin. High genetic similarity on the southern and southwestern plateau showed population expansion along the Yarlung Tsangpo River since 3400 years ago. Central and southeastern plateau populations revealed extensive genetic admixture within the plateau historically, with substantial ancestry related to that found in southern and southwestern plateau populations. Over the past ~700 years, substantial gene flow from lowland East Asia further shaped the genetic landscape of present-day plateau populations. The high-altitude adaptiveEPAS1allele was found in plateau populations as early as in a 5100-year-old individual and showed a sharp increase over the past 2800 years.