Since their arrival in the Tibetan Plateau during the Neolithic Age, Tibetans have been well-adapted to extreme environmental conditions and possess genetic variation that reflect their living environment and migratory history. To investigate the origin of Tibetans and the genetic basis of adaptation in a rigorous environment, we genotyped 30 Tibetan individuals with more than one million SNP markers. Our findings suggested that Tibetans, together with the Yi people, were descendants of Tibeto-Burmans who diverged from ancient settlers of East Asia. The valleys of the Hengduan Mountain range may be a major migration route. We also identified a set of positively-selected genes that belong to functional classes of the embryonic, female gonad, and blood vessel developments, as well as response to hypoxia. Most of these genes were highly correlated with population-specific and beneficial phenotypes, such as high infant survival rate and the absence of chronic mountain sickness.

Background and Purpose—: ANRIL has long been considered as the strongest candidate gene at the 9p21 locus, robustly associated with stroke and coronary artery disease. However, the underlying molecular mechanism remains unknown. The present study works to elucidate such a mechanism. Methods—: Using expression quantitative loci analysis, we identified potential genes whose expression may be influenced by genetic variation in ANRIL . To verify the identified gene(s), knockdown and overexpression of ANRIL were evaluated in human umbilical vein endothelial cells and HepG2 cells. Ischemic stroke and coronary artery disease risk were then evaluated in the gene(s) demonstrated to be mediated by ANRIL in 3 populations of Chinese Han ancestry: 2 ischemic stroke populations consisting of the Central China cohort (903 cases and 873 controls) and the Northern China cohort (816 cases and 879 controls) and 1 coronary artery disease cohort consisting of 772 patients and 873 controls. Results—: Expression quantitative loci analysis identified CARD8 among others, with knockdown of ANRIL expression decreasing CARD8 expression and overexpression of ANRIL increasing CARD8 expression. The minor T allele of a previously identified CARD8 variant (rs2043211) was found to be significantly associated with a protective effect of ischemic stroke under the recessive model in 2 independent stroke cohorts. No significant association was found between rs2043211 and coronary artery disease. Conclusions—: CARD8 is a downstream target gene regulated by ANRIL. Single nucleotide polymorphism rs2043211 in CARD8 is significantly associated with ischemic stroke. ANRIL may increase the risk of ischemic stroke through regulation of the CARD8 pathway.

Circadian disruptions may result in sleep problems, oxidative stress and an altered inflammatory response. These symptoms may contribute to PD pathogenesis, despite a lack of direct experimental evidence supporting this relationship. Clock genes are essential to drive and maintain circadian rhythm. To elucidate the possible role of circadian disruptions in PD, we investigated 132 tag variants in eight clock genes. We genotyped these tags within 1,394 Chinese cases and 1,342 controls using Illumina GoldenGate chips. We discovered that SNPs inARNTL(rs900147,P = 3.33 × 10⁻⁵, OR = 0.80) andPER1(rs2253820,P = 5.30 × 10⁻⁶, OR = 1.31) genes are significantly associated with PD risk. Moreover, the positive association of theARNTLrs900147 variant was more robust in tremor dominant (TD) (P = 3.44 × 10⁻⁴) than postural instability and gait difficulty (PIGD) cases (P = 6.06 × 10⁻²). The association of thePER1rs2253820 variant was more robust in PIGD (P = 5.42 × 10⁻⁵) than TD cases (P = 4.2 × 10⁻²). Haplotype analysis also showed thatARNTLandPER1were associated with PD. Imputation analysis identified more SNPs withinARNTLandPER1associated with PD, some of which may affect gene expression through altering the transcription factor binding site. In summary, our findings suggest that genetic polymorphisms inARNTLandPER1genes, as well as circadian disruptions, may contribute to PD pathogenesis.

Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa