Association study (especially the genome-wide association study) now has a key function in identification and characterization of disease-predisposing genetic variant(s), which customarily involve multiple single nucleotide polymorphisms (SNPs) in a candidate region or across the genome. Case-control association design remains the most popular and a challenging issue in the statistical analysis is the optimal use of all information contained in these SNPs. Previous approaches often treated gene-gene interaction as deviation from additive genetic effects or replaced it with SNP-SNP interaction. However, these approaches are limited for their failure of consideration of gene-gene interaction or gene-gene co-association at gene level. Although the co-association of the SNPs within a candidate gene can be detected by principal component analysis-based logistic regression model, the detection of co-association between genes in genome remains uncertain. Here, we proposed a canonical correlationbased U statistic (CCU) for detecting gene-based gene-gene co-association in the case-control design. We explored its type I error rates and power through simulation and analyzed two real data sets. By treating gene as a functional unit in analysis, we found that CCU was a strong alternative to previous approaches. We discussed the performance of CCU as a gene-based gene-gene co-association statistic and the prospect of further improvement.

Hair straightness/curliness is one of the most conspicuous features of human variation and is particularly diverse among populations. A recent genome-wide scan found common variants in the Trichohyalin (TCHH) gene that are associated with hair straightness in Europeans, but different genes might affect this phenotype in other populations. By sampling 2899 Han Chinese, we performed the first genome-wide scan of hair straightness in East Asians, and found EDAR (rs3827760) as the predominant gene (P = 4.67 × 10), accounting for 3.66 % of the total variance. The candidate gene approach did not find further significant associations, suggesting that hair straightness may be affected by a large number of genes with subtle effects. Notably, genetic variants associated with hair straightness in Europeans are generally low in frequency in Han Chinese, and vice versa. To evaluate the relative contribution of these variants, we performed a second genome-wide scan in 709 samples from the Uyghur, an admixed population with both eastern and western Eurasian ancestries. In Uyghurs, both EDAR (rs3827760: P = 1.92 × 10) and TCHH (rs11803731: P = 1.46 × 10) are associated with hair straightness, but EDAR (OR 0.415) has a greater effect than TCHH (OR 0.575). We found no significant interaction between EDAR and TCHH (P = 0.645), suggesting that these two genes affect hair straightness through different mechanisms. Furthermore, haplotype analysis indicates that TCHH is not subject to selection. While EDAR is under strong selection in East Asia, it does not appear to be subject to selection after the admixture in Uyghurs. These suggest that hair straightness is unlikely a trait under selection.

High altitude acclimatization is a series of physiological responses taking places when subjects go to altitude. Many factors could influence these processes, such as altitude, ascending speed and individual characteristics. In this study, based on a repeated measurement design of three sequential measurements at baseline, acute phase and chronic phase, we evaluated the effect of BMI, smoking and drinking on a number of physiological responses in high altitude acclimatization by using mixed model and partial least square path model on a sample of 755 Han Chinese young males. We found that subjects with higher BMI responses were reluctant to hypoxia. The effect of smoking was not significant at acute phase. But at chronic phase, red blood cell volume increased less while respiratory function increased more for smoking subjects compared with nonsmokers. For drinking subjects, red blood cell volume increased less than nondrinkers at both acute and chronic phases, while blood pressures increased more than nondrinkers at acute phase and respiratory function, red blood cell volume and oxygen saturation increased more than nondrinkers at chronic phase. The heavy and long-term effect of smoking, drinking and other factors in high altitude acclimatization needed to be further studied.

Regulatory variants of the MTR gene increase CHD risk by reducing MTR expression and inducing the homocysteine accumulation and elevation.

Background: The progression of human skin aging has a strong genetic basis. However, recent studies have mainly focused on Caucasian populations and we have thus performed a genetic association study on skin aging signs in Han Chinese population. Objective: To investigate genetic risk factors in skin aging in Han Chinese female, we performed a genome-wide association study. Methods: We collected genotype data from 1534 Han Chinese female from Taizhou cohort and evaluated 15 skin aging phenotypes by using the validated skin aging SCINEXA TM score. Genetic associations were tested by linear and logistic regression analyses and adjusted for potential confounders. Results: Six genomic regions significantly associated with a risk for skin aging were revealed : 6q24.2 (rs3804540, P = 4.6 Â 10 À9 , additive model) with size of pigmented spots on forehead, 10q26.13 (rs4962295, P = 1.9 Â 10 À8 , additive model) with wrinkles under eyes, 15q21.1 (rs28392847, P = 1.6 Â 10 À8 , additive model) with crow's feet, 2p25.1 (rs191497052, P = 5.5 Â 10 À9 , dominant model) with telangiectasia, 13q34 (rs3825460, P = 3.7 Â 10 À8 , dominant model) with size of pigmented spots on cheeks and 16p13.11(rs76053540, P = 5.0 Â 10 À9 , dominant model) with nasolabialfold. The signal on 15q21.1 was replicated in the meta-analysis with two independent Caucasian cohorts (P = 8.6 Â 10 À10 ). We have also successfully replicated in our cohort an association between SNP rs1048943 of gene CYP1A1 (P = 7.1 Â 10 -4 ) and pigmented spots on cheeks previously described in Caucasian cohort. Conclusions: Our study has identified new genetic risk factors for signs of skin aging in the Han Chinese. This study suggests there are differences in genetic susceptibility to skin aging between Caucasians and the Han Chinese.

An adaptive variant of human Ectodysplasin receptor, EDARV370A, had undergone strong positive selection in East Asia. In mice and humans, EDARV370A was found to affect ectodermal-derived characteristics, including hair thickness, hair shape, active sweat gland density and teeth formation. Facial characteristics are also largely ectodermal derived. In this study, taking advantage of an admixed population of East Asian and European ancestry-the Uyghur, we aim to test whether EDARV370A is affecting facial characteristics and to investigate its pleiotropic nature and genetic model. In a sample of 1027 Uyghurs, we discover that EDARV370A is significantly associated with several facial characteristics, in particular shape of earlobe (P = 3.64 × 10 (-6) ) and type of chin (P = 9.23 × 10 (-5) ), with successful replication in other East Asian populations. Additionally, in this Uyghur population, we replicate previous association findings of incisors shoveling (P = 1.02 × 10 (-7) ), double incisors shoveling (P = 1.86 × 10 (-12) ) and hair straightness (P = 3.99 × 10 (-16) ), providing strong evidence supporting an additive model for the EDARV370A associations. Partial least square path model confirms EDARV370A systematically affect these weakly related ectodermal-derived characteristics, suggesting the pleiotropic effect of EDARV370A mainly plays roles in early embryo development. This study extends our knowledge about the pleiotropic nature of EDARV370A and provides potential clues to its adaptation fitness in human evolution.

Summary Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized “pattern-block” correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.

Facial morphology, a conspicuous feature of human appearance, is highly heritable. Previous studies on the genetic basis of facial morphology were mainly performed in European-ancestry cohorts (EUR). Applying a data-driven phenotyping and multivariate genome-wide scanning protocol to a large collection of 3D facial images of individuals with East Asian ancestry (EAS), we identified 244 variants in 166 loci (62 novel) associated with typical-range facial variation. A newly proposed polygenic shape analysis indicates that the effects of the variants on facial shape in EAS can be generalized to EUR. Based on this, we further identified 13 variants related to differences between facial shape in EUR and EAS populations. Evolutionary analyses suggest that the difference in nose shape in EUR and EAS populations is caused by a directional selection, mainly due to a local adaptation in Europeans. Our results illustrate the underlying genetic basis for facial differences across populations.