High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele.

For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies have provided evidence for positive selection acting in Andeans on the HIF2A (also known as EPAS1) locus, which encodes for a central transcription factor of the hypoxia-inducible factor pathway. However, the precise mechanism by which this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes, we confirm evidence for positive selection acting on HIF2A and a unique pattern of variation surrounding the Andean-specific single nucleotide variant (SNV), rs570553380, which encodes for an H194R amino acid substitution in HIF-2α. Genotyping the Andean-associated SNV rs570553380 in a group of 299 Peruvian Andeans from Cerro de Pasco, Peru (4,338 m), reveals a positive association with increased fraction of exhaled nitric oxide, a marker of nitric oxide biosynthesis. In vitro assays show that the H194R mutation impairs binding of HIF-2α to its heterodimeric partner, aryl hydrocarbon receptor nuclear translocator. A knockin mouse model bearing the H194R mutation in the Hif2a gene displays decreased levels of hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. We conclude the Andean H194R HIF2A allele is a hypomorphic (partial loss of function) allele.

The Legacy of Infectious Disease Exposure on the Genomic Diversity of Indigenous Southern Mexicans.

To characterize host risk factors for infectious disease in Mesoamerican populations, we interrogated 857,481 SNPs assayed using the Affymetrix 6.0 genotyping array for signatures of natural selection in immune response genes. We applied three statistical tests to identify signatures of natural selection: locus-specific branch length (LSBL), the cross-population extended haplotype homozygosity (XP-EHH), and the integrated haplotype score (iHS). Each of the haplotype tests (XP-EHH and iHS) were paired with LSBL and significance was determined at the 1% level. For the paired analyses, we identified 95 statistically significant windows for XP-EHH/LSBL and 63 statistically significant windows for iHS/LSBL. Among our top immune response loci, we found evidence of recent directional selection associated with the major histocompatibility complex (MHC) and the peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathway. These findings illustrate that Mesoamerican populations' immunity has been shaped by exposure to infectious disease. As targets of selection, these variants are likely to encode phenotypes that manifest themselves physiologically and therefore may contribute to population-level variation in immune response. Our results shed light on past selective events influencing the host response to modern diseases, both pathogenic infection as well as autoimmune disorders.

Identifying adaptive alleles in the human genome: from selection mapping to functional validation.

The suite of phenotypic diversity across geographically distributed human populations is the outcome of genetic drift, gene flow, and natural selection throughout human evolution. Human genetic variation underlying local biological adaptations to selective pressures is incompletely characterized. With the emergence of population genetics modeling of large-scale genomic data derived from diverse populations, scientists are able to map signatures of natural selection in the genome in a process known as selection mapping. Inferred selection signals further can be used to identify candidate functional alleles that underlie putative adaptive phenotypes. Phenotypic association, fine mapping, and functional experiments facilitate the identification of candidate adaptive alleles. Functional investigation of candidate adaptive variation using novel techniques in molecular biology is slowly beginning to unravel how selection signals translate to changes in biology that underlie the phenotypic spectrum of our species. In addition to informing evolutionary hypotheses of adaptation, the discovery and functional annotation of adaptive alleles also may be of clinical significance. While selection mapping efforts in non-European populations are growing, there remains a stark under-representation of diverse human populations in current public genomic databases, of both clinical and non-clinical cohorts. This lack of inclusion limits the study of human biological variation. Identifying and functionally validating candidate adaptive alleles in more global populations is necessary for understanding basic human biology and human disease.

The inflammatory gene pathway is not a major contributor to polycystic ovary snydrome.

CONTEXT: Although inflammation is clearly associated with obesity, diabetes, and insulin resistance, the role of chronic inflammation in the etiology of polycystic ovary syndrome (PCOS) is unclear. OBJECTIVE: To determine whether chronic inflammation plays a causal role in the etiology of PCOS, we tested for an association between PCOS and genetic markers mapping to 80 members of the inflammatory pathway. DESIGN: This was a case-control association study. SETTING: The setting was an academic medical center. PATIENTS OR PARTICIPANTS: A total of 905 index case patients with PCOS and 955 control women (108 intensively phenotyped subjects with normal androgen levels and regular menses and 847 minimally phenotyped subjects with regular menses and no history of PCOS). INTERVENTIONS: Subjects were genotyped at single nucleotide polymorphisms mapping to 80 inflammatory genes. Logistic regression was used to test for an association between 822 single nucleotide polymorphisms and PCOS after adjustment for population stratification, body mass index, and/or age. In the index patients, we also tested for association with 11 quantitative traits (body mass index and testosterone, fasting insulin, fasting glucose, 2-hour postchallenge glucose, LH, FSH, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels). MAIN OUTCOME MEASURES: The evidence for an association with PCOS and with 11 quantitative traits was investigated. RESULTS: Nominally significant evidence for an association was observed with MAP3K7, IKBKG, TNFRS11A, AKT2, IL6R, and IRF1, but no results remained statistically significant after adjustment for multiple testing. CONCLUSIONS: Genetic variation in the inflammatory pathway is not a major contributor to the etiology of PCOS or related quantitative traits in women with PCOS.

Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry.

CONTEXT: A previous genome-wide association study in Chinese women with polycystic ovary syndrome (PCOS) identified a region on chromosome 2p16.3 encoding the LH/choriogonadotropin receptor (LHCGR) and FSH receptor (FSHR) genes as a reproducible PCOS susceptibility locus. OBJECTIVE: The objective of the study was to determine the role of the LHCGR and/or FSHR gene in the etiology of PCOS in women of European ancestry. DESIGN: This was a genetic association study in a European ancestry cohort of women with PCOS. SETTING: The study was conducted at an academic medical center. PARTICIPANTS: Participants in the study included 905 women with PCOS diagnosed by National Institutes of Health criteria and 956 control women. INTERVENTION: We genotyped 94 haplotype-tagging single-nucleotide polymorphisms and two coding single-nucleotide polymorphisms mapping to the coding region of LHCGR and FSHR plus 20 kb upstream and downstream of the genes and test for association in the case control cohort and for association with nine quantitative traits in the women with PCOS. RESULTS: We found strong evidence for an association of PCOS with rs7562215 (P = 0.0037) and rs10495960 (P = 0.0046). Although the marker with the strongest association in the Chinese PCOS genome-wide association study (rs13405728) was not informative in the European populations, we identified and genotyped three markers (rs35960650, rs2956355, and rs7562879) within 5 kb of rs13405728. Of these, rs7562879 was nominally associated with PCOS (P = 0.020). The strongest evidence for association mapping to FSHR was observed with rs1922476 (P = 0.0053). Furthermore, markers with the FSHR gene region were associated with FSH levels in women with PCOS. CONCLUSIONS: Fine mapping of the chromosome 2p16.3 Chinese PCOS susceptibility locus in a European ancestry cohort provides evidence for association with two independent loci and PCOS. The gene products LHCGR and FSHR therefore are likely to be important in the etiology of PCOS, regardless of ethnicity.

Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterised by hyperandrogenaemia and irregular menses. A recent genome-wide association study (GWAS) of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinising hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined. METHODS AND RESULTS: The study tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European derived PCOS cohorts (cohort A = 939 cases and 957 controls; cohort B = 535 cases and 845 controls). Cases fulfilled the National Institute of Child Health & Human Development criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in the study cohort (p(combined cohorts)=10(-8)); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. The present study had >80% power to detect an effect of similar size as was observed by Chen et al for DENND1A and THADA, but reduced power (at <40%) for LHCGR at p=0.0001. The study had sufficient power (57-88%) for LHCGR at p=0.01. CONCLUSIONS: At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European derived populations, and are therefore likely to be important in the aetiology of PCOS regardless of ethnicity. The analysis of the LHCGR gene was not sufficiently powered to detect modest effects.