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Supplementary Figure 1. An overview of the study workflow; Supplementary Figure 2. The principal components analyses (PCA) of samples in the discovery stage and reference samples from the 1000 Genomes Project data. Supplementary Figure 3. Manhattan plots of the genome-wide P values from the association tests on HBV-related HCC. Supplementary Figure 4. Quantile-quantile plots of the observed P values from the association tests on HBV-related HCC. Supplementary Figure 5. Forest plots for rs10272859 across all studies. Supplementary Figure 6. Expression levels of CDK14 mRNA were significantly higher in HCC tissues compared with adjacent non-tumor liver tissues. Supplementary Figure 7. The at-risk G allele of rs10272859 was significantly associated with higher mRNA levels of CDK14 in liver tissues based on the TCGA data. Supplementary Figure 8. The SNPs at 7q21.13 interact physically with the promoter region of CDK14 in GM12878 cells. Supplementary Figure 9. Kaplan-Meier estimates of the overall survival time for the HCC patients stratified by CDK14 mRNA expression levels. Supplementary Figure 10. Kaplan-Meier estimates of disease-free survival time for patients with HBV-related HCC stratified by genotypes of rs10272859. Supplementary Table 1. Summary description of the populations used in this study. Supplementary Table 2. Summary of the quality controls in proband-parent trios. Supplementary Table 3. Summary of SNP imputation in the discovery stage. Supplementary Table 4. The amount of SNPs with various P values in TDT for the 189 trios in the discovery stage. Supplementary Table 5. Summary of the SNPs that have been reported significantly associated with HBV-related HCC in previous GWASs. Supplementary Table 6. Summary of SNPs that have been reported to be significantly associated with HBV-related phenotypes in previous GWASs. Supplementary Table 6. Summary of SNPs that have been reported to be significantly associated with HBV-related phenotypes in previous GWASs (Continued). Supplementary Table 7. Summary of the top 15 SNPs in the discovery stage. Supplementary Table 8. Primers and probes used in this study. Supplementary Table 9. Summary of the replication studies for the 14 SNPs newly identified in the discovery stage. Supplementary Table 10. Stratification analyses of rs10272859 by gender and age. Supplementary Table 11. The associations between genotypes of rs10272859 and mRNA levels of nearby genes. Supplementary Table 12. The predicted functional relevance of rs10272859 and the other 74 SNPs in strong linkage disequilibrium with rs10272859 at the ~110 Kb region of 7q21.13. Supplementary Table 13. Details for the genotypes of rs10272859 and the prognosis of patients with HBV-related HCC. Supplementary Table 14. Multivariate analyses of overall survival time and disease-free survival time of patients with HBV-related HCC. Supplementary Table 15. Genotype distribution of rs10272859 across TNM stages in patients with HBV-related HCC. Supplementary Table 16. Powers for various genetic effects and various minor allele frequencies. Supplementary Table 17. The allele and genotype frequencies of rs10272859 in different populations.

Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In this study, we performed a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC.Experimental Design: GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls.Results: We identified a novel association signal within the CDK14 gene at 7q21.13 (index rs10272859, OR = 1.28, P = 9.46 × 10−10). Furthermore, we observed that the at-risk rs10272859[G] allele was significantly associated with higher mRNA expression levels of CDK14 in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of CDK14 and the risk-associated SNPs in strong linkage disequilibrium with the index rs10272859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients.Conclusions: Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the CDK14 gene to be the functional target of the 7q21.13 locus. Clin Cancer Res; 24(4); 906–15. ©2017 AACR.

High-altitude polycythemia (HAPC) is characterized by excessive proliferation of erythrocytes, resulting from the hypobaric hypoxia condition in high altitude. The genetic variants and molecular mechanisms of HAPC remain unclear in highlanders. We recruited 141 Tibetan dwellers, including 70 HAPC patients and 71 healthy controls, to detect the possible genetic variants associated with the disease; and performed targeted sequencing on 529 genes associated with the oxygen metabolism and erythrocyte regulation, utilized unconditional logistic regression analysis and GO (gene ontology) analysis to investigate the genetic variations of HAPC. We identified 12 single nucleotide variants, harbored in 12 genes, associated with the risk of HAPC (4.7 ≤ odd ratios ≤ 13.6; 7.6E − 08 ≤ p-value ≤ 1E − 04). The pathway enrichment study of these genes indicated the three pathways, the PI3K-AKT pathway, JAK-STAT pathway, and HIF-1 pathway, are essential, which p-values as 3.70E − 08, 1.28 E − 07, and 3.98 E − 06, respectively. We are hopeful that our results will provide a reference for the etiology research of HAPC. However, additional genetic risk factors and functional investigations are necessary to confirm our results further.

Objectives: Genome-wide association studies have identified a significant risk gene, CACNA1C, for schizophrenia. In this study, we comprehensively investigated a large set of CACNA1C single-nucleotide polymorphisms (SNPs) to identify the replicable risk alleles for schizophrenia and explore their biological functions. Methods: One Jewish (1044 cases vs 2052 controls), one European (1350 cases vs 1378 controls) and one exploratory African American samples (98 cases vs 20 controls) were analyzed to identify replicable single-nucleotide polymorphism–schizophrenia associations. The regulatory effects of risk alleles on CACNA1C messenger RNA expression were examined. The most robust risk tagSNP (rs1006737) was meta-analyzed on 17 studies (74,122 cases vs 109,062 controls), and associated with the gray matter volumes of seven subcortical structures in 38,258 Europeans, and the surface areas and thickness of 34 cortical regions in 33,992 Europeans and 2944 non-Europeans. Results: Forty-seven replicable risk single-nucleotide polymorphisms, including a 20-single-nucleotide polymorphism haplotype block, were identified in our samples (1.8 × 10−4 ⩽ p ⩽ 0.049). This variant block was consistently associated with schizophrenia across four independent Psychiatric Genomics Consortium cohorts (79,645 cases vs 109,590 controls; 2.5 × 10–17 ⩽ p ⩽ 0.017). This block showed significant expression quantitative trait loci in three independent European brain cohorts (5.1 × 10–12 ⩽ p ⩽ 8.3 × 10–3) and could be tagged by the most significant risk single-nucleotide polymorphism rs1006737. The minor allele A of rs1006737 significantly increased risk for schizophrenia across the Jewish and European samples ( p = 0.029 and 0.004, respectively), and this association was highly significant in the meta-analysis ( p = 1.62 × 10–42). This allele also significantly altered the CACNA1C messenger RNA expression in five brain regions (5.1 × 10–12 ⩽ p ⩽ 0.05), decreased the gray matter volume of thalamus ( p = 0.010), the surface area of isthmus cingulate cortex ( p = 0.013) and the thickness of transverse temporal and superior temporal sulcus cortexes (0.005 ⩽ p ⩽ 0.043). Conclusion: We identified an independent, replicable, functional, and significant risk variant block at CACNA1C for schizophrenia, which could be tagged by the most robust risk marker rs1006737, suggesting an important role of CACNA1C in the pathogenesis of schizophrenia.

Tibetan, one of the largest indigenous populations living in the high-altitude region of the Tibetan Plateau (TP), has developed a suite of physiological adaptation strategies to cope with the extreme highland environment in TP. To comprehensively characterize the genetic origin and detailed evolutionary profiles of Tibetan highlanders, here, we reported genome-wide SNP data from 62 Nagqu Tibetans who belong to U-Tsang Tibetan groups but speak Kham Tibetan dialect, and analyzed together with published data from 1,067 individuals in 167 modern and ancient populations. Overall, patterns of alleles sharing suggested (1) the relatively genetic homogeny between studied Nagqu Tibetans and published U-Tang Tibetans from Lhasa, Nagqu, Shannan, and Shigatse, as well as ancient Nepals; (2) the genomic connection between lowland present-day northern Han Chinese/ancient millet farmers and highland Tibetans. The IBD sharing profiles validated the shared demographic history between Kham-speaking Tibetans and U-Tsang Tibetans as well as Kham-speaking Chamdo Tibetans. The fitted qpAdm models showed that studied Tibetans could be fitted as having the main ancestry from late Neolithic upper Yellow River Qijia millet farmers and deep ancestries from Southern East Asians, with a non-neglectable western Steppe-related ancestry (~3%). We further scanned the selection-candidate genomic regions via iHS and XP-EHH tests based on two different SNP panels and identified several putative genomic candidate genes associated with essential human biological functions such as immune response, enzyme activity, signal transduction.

The deep population history of East Asia remains poorly understood owing to a lack of ancient DNA data and sparse sampling of present-day people1,2. Here we report genome-wide data from 166 East Asian individuals dating to between 6000 bc and ad 1000 and 46 present-day groups. Hunter-gatherers from Japan, the Amur River Basin, and people of Neolithic and Iron Age Taiwan and the Tibetan Plateau are linked by a deeply splitting lineage that probably reflects a coastal migration during the Late Pleistocene epoch. We also follow expansions during the subsequent Holocene epoch from four regions. First, hunter-gatherers from Mongolia and the Amur River Basin have ancestry shared by individuals who speak Mongolic and Tungusic languages, but do not carry ancestry characteristic of farmers from the West Liao River region (around 3000 bc), which contradicts theories that the expansion of these farmers spread the Mongolic and Tungusic proto-languages. Second, farmers from the Yellow River Basin (around 3000 bc) probably spread Sino-Tibetan languages, as their ancestry dispersed both to Tibet—where it forms approximately 84% of the gene pool in some groups—and to the Central Plain, where it has contributed around 59–84% to modern Han Chinese groups. Third, people from Taiwan from around 1300 bc to ad 800 derived approximately 75% of their ancestry from a lineage that is widespread in modern individuals who speak Austronesian, Tai–Kadai and Austroasiatic languages, and that we hypothesize derives from farmers of the Yangtze River Valley. Ancient people from Taiwan also derived about 25% of their ancestry from a northern lineage that is related to, but different from, farmers of the Yellow River Basin, which suggests an additional north-to-south expansion. Fourth, ancestry from Yamnaya Steppe pastoralists arrived in western Mongolia after around 3000 bc but was displaced by previously established lineages even while it persisted in western China, as would be expected if this ancestry was associated with the spread of proto-Tocharian Indo-European languages. Two later gene flows affected western Mongolia: migrants after around 2000 bc with Yamnaya and European farmer ancestry, and episodic influences of later groups with ancestry from Turan. Genome-wide data from 166 East Asian individuals dating to between 6000 bc and ad 1000 and from 46 present-day groups provide insights into the histories of mixture and migration of human populations in East Asia.

Altitude acclimatization is a human physiological process of adjusting to the decreased oxygen availability. Since several physiological processes are involved and their correlations are complicated, the analyses of single traits are insufficient in revealing the complex mechanism of high-altitude acclimatization. In this study, we examined these physiological responses as the composite phenotypes that are represented by a linear combination of physiological traits. We developed a strategy that combines both spectral clustering and partial least squares path modeling (PLSPM) to define composite phenotypes based on a cohort study of 883 Chinese Han males. In addition, we captured 14 composite phenotypes from 28 physiological traits of high-altitude acclimatization. Using these composite phenotypes, we applied k-means clustering to reveal hidden population physiological heterogeneity in high-altitude acclimatization. Furthermore, we employed multivariate linear regression to systematically model (Models 1 and 2) oxygen saturation (SpO2) changes in high-altitude acclimatization and evaluated model fitness performance. Composite phenotypes based on Model 2 fit better than single trait-based Model 1 in all measurement indices. This new strategy of using composite phenotypes may be potentially employed as a general strategy for complex traits research such as genetic loci discovery and analyses of phenomics.

Background Coronavirus disease 2019 (COVID‐19) has had a devastating impact on public health services worldwide. Currently, there are no standard remedies or therapies for COVID‐19. it is important to identify and diagnose COVID‐19 to control the spread. But clinical symptoms of COVID‐19 are very similar to those of other respiratory viruses. Results As a result, the diagnosis of COVID‐19 relies heavily on detecting pathogens. We established a bunch of triplex new TaqMan real‐time PCR assays. Three sets of primers and probes (targeting the ORF1ab, N, and E genes, respectively) are poorly consistent with other human coronaviruses and the human influenza virus. The sensitivity of established PCR assays notices as few as 100 copies per PCR of the ORF1ab, N, and E genes. Meanwhile, standard curves concluded from constant PCR reaction all showed glorious linear correlations between Ct values and the polymer loading copy variety (correlation coefficient (R2) of ORF1ab, N, and E genes is 0.996, 0.991, and 0.998, respectively). Surveillance of RNA‐based pseudovirus demonstrated that they were identified to be positive with respect to SARS‐CoV‐2 and that established PCR assays are achievable. Conclusion The assays established provide a smaller reaction volume for diagnosing COVID‐19., In this work, We established a bunch of triplex new TaqMan real‐time PCR assays. Three sets of primers and probes (targeting the ORF1ab, N and E genes, respectively) are poorly consistent with other human coronaviruses and the human influenza virus. Surveillance of RNA‐based pseudovirus demonstrated that they were identified positive with respect to SARS‐CoV‐2, and the established PCR assays is achievable. The assays established provides a smaller reaction volume for diagnosing COVID‐19.

Background Diet, environment, and genomic context have a significant impact on humans’ intestinal microbiota. Moreover, migration may be accompanied by changes in human eating habits and living environment, which could, in turn, affect the intestinal microbiota. Located in southwestern China, Tibet has an average altitude of 4,000 meters and is known as the world’s roof. Xianyang is situated in the plains of central China, with an average altitude of about 400 meters. Methods To understand the association between intestinal microbiota and population migration, we collected the fecal samples from 30 Tibetan women on the first day (as TI1st), six months (as TI2nd), and ten months (as TI3rd) following migration from Tibet to Xianyang. Fecal samples were collected from 29 individuals (belonging to the Han women) as a control. The dietary information of the Tibetan women and the Han women was gathered. We performed a 16S rRNA gene survey of the collected fecal samples using Illumina MiSeq sequencing. Results Following the migration, the alpha and beta diversity of Tibetan women’s intestinal microbiota appeared unaffected. Linear discriminant analysis effect size (LEfSe) analysis showed that Klebsiella, Blautia, and Veillonella are potential biomarkers at TI1st, while Proteobacteria and Enterobacteriaceae were common in TI3rd. Finally, functional prediction by phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) found no significant up-regulation or down-regulation gene pathway in the intestinal microbiota of Tibetan women after migration. The present study reveals that the higher stability in Tibetan women’s intestinal microbiota was less affected by the environment and diet, indicating that Tibetan women’s intestinal microbiota is relatively stable. The main limitations of the study were the small sample size and all volunteers were women.

Genome-wide association studies (GWASs) have reported numerous associations between risk variants and major psychiatric disorders (MPDs) including schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD) and others. We reviewed all of the published GWASs, and extracted the genome-wide significant (p10

Genome-wide association studies have identified a significant risk gene,One Jewish (1044 cases vs 2052 controls), one European (1350 cases vs 1378 controls) and one exploratory African American samples (98 cases vs 20 controls) were analyzed to identify replicable single-nucleotide polymorphism-schizophrenia associations. The regulatory effects of risk alleles onForty-seven replicable risk single-nucleotide polymorphisms, including a 20-single-nucleotide polymorphism haplotype block, were identified in our samples (1.8 × 10We identified an independent, replicable, functional, and significant risk variant block at

Human genetic adaptation to high altitudes (>2500 m) has been extensively studied over the last few years, but few functional adaptive genetic variants have been identified, largely owing to the lack of deep-genome sequencing data available to previous studies. Here, we build a list of putative adaptive variants, including 63 missense, 7 loss-of-function, 1,298 evolutionarily conserved variants and 509 expression quantitative traits loci. Notably, the top signal of selection is located in TMEM247, a transmembrane protein-coding gene. The Tibetan version of TMEM247 harbors one high-frequency (76.3%) missense variant, rs116983452 (c.248C > T; p.Ala83Val), with the T allele derived from archaic ancestry and carried by >94% of Tibetans but absent or in low frequencies (

Objectives The Hui people are the adherents of Muslim faith and distributing throughout China. There are two contrasting hypotheses about the origin and diversification of the Hui people, namely, the demic diffusion involving the mass movement of people or simple cultural diffusion. Materials and methods We collected 621 unrelated male individuals from 23 Hui populations all over China. We comprehensively genotyped more than 100 informative Y-chromosomal single nucleotide polymorphisms and 17 Y-chromosomal short tandem repeats (STRs) on those samples. Results Co-analyzed with published worldwide populations, our results suggest the origin of Hui people has involved massive assimilation of indigenous East Asians with about 70% in total of the paternal ancestry could be traced back to East Asia and the left 30% to various regions in West Eurasia. Discussion The genetic structure of the extant Hui populations was primarily shaped by the indigenous East Asian populations as they contribute the majority part of the paternal lineages of Hui people. The West Eurasian admixture was probably a sex-biased male-driven process since we have not found such a high proportion of West Eurasian gene flow on autosomal STRs and maternal mtDNA.

A special fluorescent probe has been developed, one that demonstrated excellent “off-on-type” change in fluorescence with high selectivity toward Cu2+. Interestingly, the probe–Cu2+ complex could detect cysteine due to the ability of this amino acid to strongly coordinate Cu2+, and no obvious interference was observed from other amino acids and anions. According to the proposed mechanism, addition of cysteine induced decomplexation of the probe–Cu2+ form. Furthermore, the results of confocal microscopy experiments demonstrated the potential of using the probe to image Cu2+ in living cells and mice.

Human oral microbes play a vital role maintaining host metabolic homeostasis. The Qinghai-Tibet Plateau is mainly characterized by a high altitude, dry, cold, and hypoxic environment. The oral microbiota is subject to selective pressure from the plateau environment, which affects oral health. Only a few studies have focused on the characteristics of oral microbiota in high-altitude humans. We collected saliva samples from 167 Tibetans at four altitudes (2800 to 4500 m) in Tibet to explore the relationship between the high altitude environment and oral microbiota. We conducted a two (high- and ultra-high-altitude) group analysis based on altitude, and adopted the 16S rRNA strategy for high-throughput sequencing. The results show that the alpha diversity of the oral microbiota decreased with altitude, whereas beta diversity increased with altitude. A LEfSe analysis revealed that the oral microbial biomarker of the high-altitude group (Streptococcus, and the biomarker of the ultra-high-altitude group (> 4000 m) was Prevotella. The relative abundance of Prevotella increased with altitude, whereas the relative abundance of Streptococcus decreased with altitude. A network analysis showed that the microbial network structure was more compact and complex, and the interaction between the bacterial genera was more intense in the high altitude group. Gene function prediction results showed that the amino acid and vitamin metabolic pathways were upregulated in the ultra-high-altitude group. These result show that altitude is an important factor affecting the diversity and community structure of the human oral microbiota.

Supplemental material, sj-docx-1-anp-10.1177_00048674211009595 for An independent, replicable, functional and significant risk variant block at intron 3 of CACNA1C for schizophrenia by Zuxing Wang, Wenzhong Chen, Yuping Cao, Yikai Dou, Yingmei Fu, Yong Zhang, Xingqun Luo, Longli Kang, Na Liu, Yun Stone Shi, Chiang-shan R Li, Yifeng Xu, Xiaoyun Guo and Xingguang Luo in Australian & New Zealand Journal of Psychiatry

Background Selective loss of dopaminergic neurons and diminished putamen gray matter volume (GMV) represents a central feature of Parkinson’s disease (PD). Recent studies have reported specific effects of kinectin 1 gene (KTN1) variants on the putamen GMV. Objective To examine the relationship of KTN1 variants, KTN1 mRNA expression in the putamen and substantia nigra pars compacta (SNc), putamen GMV, and PD. Methods We examined the associations between PD and a total of 1847 imputed KTN1 single nucleotide polymorphisms (SNPs) in one discovery sample [2,000 subjects with PD vs. 1,986 healthy controls (HC)], and confirmed the nominally significant associations (p < 0.05) in two replication samples (900 PD vs. 867 HC, and 940 PD vs. 801 HC, respectively). The regulatory effects of risk variants on the KTN1 mRNA expression in putamen and SNc and the putamen GMV were tested. We also quantified the expression levels of KTN1 mRNA in the putamen and/or SNc for comparison between PD and HC in five independent cohorts. Results Six replicable and two non-replicable KTN1-PD associations were identified (0.009 ≤ p ≤ 0.049). The major alleles of five SNPs, including rs12880292, rs8017172, rs17253792, rs945270, and rs4144657, significantly increased risk for PD (0.020 ≤ p ≤ 0.049) and putamen GMVs (19.08 ≤ β ≤ 60.38; 2.82 ≤ Z ≤ 15.03; 5.0 × 10–51 ≤ p ≤ 0.018). The risk alleles of five SNPs, including rs8017172, rs17253792, rs945270, rs4144657, and rs1188184 also significantly increased the KTN1 mRNA expression in the putamen or SNc (0.021 ≤ p ≤ 0.046). The KTN1 mRNA was abundant in the putamen and/or SNc across five independent cohorts and differentially expressed in the SNc between PD and HC in one cohort (p = 0.047). Conclusion There was a consistent, significant, replicable, and robust positive relationship among the KTN1 variants, PD risk, KTN1 mRNA expression in putamen, and putamen volumes, and a modest relation between PD risk and KTN1 mRNA expression in SNc, suggesting that KTN1 may play a functional role in the development of PD.

The deep population history of East Asia remains poorly understood due to a lack of ancient DNA data and sparse sampling of present-day people. We report genome-wide data from 191 individuals from Mongolia, northern China, Taiwan, the Amur River Basin and Japan dating to 6000 BCE – 1000 CE, many from contexts never previously analyzed with ancient DNA. We also report 383 present-day individuals from 46 groups mostly from the Tibetan Plateau and southern China. We document how 6000-3600 BCE people of Mongolia and the Amur River Basin were from populations that expanded over Northeast Asia, likely dispersing the ancestors of Mongolic and Tungusic languages. In a time transect of 89 Mongolians, we reveal how Yamnaya steppe pastoralist spread from the west by 3300-2900 BCE in association with the Afanasievo culture, although we also document a boy buried in an Afanasievo barrow with ancestry entirely from local Mongolian hunter-gatherers, representing a unique case of someone of entirely non-Yamnaya ancestry interred in this way. The second spread of Yamnaya-derived ancestry came via groups that harbored about a third of their ancestry from European farmers, which nearly completely displaced unmixed Yamnaya-related lineages in Mongolia in the second millennium BCE, but did not replace Afanasievo lineages in western China where Afanasievo ancestry persisted, plausibly acting as the source of the early-splitting Tocharian branch of Indo-European languages. Analyzing 20 Yellow River Basin farmers dating to ∼3000 BCE, we document a population that was a plausible vector for the spread of Sino-Tibetan languages both to the Tibetan Plateau and to the central plain where they mixed with southern agriculturalists to form the ancestors of Han Chinese. We show that the individuals in a time transect of 52 ancient Taiwan individuals spanning at least 1400 BCE to 600 CE were consistent with being nearly direct descendants of Yangtze Valley first farmers who likely spread Austronesian, Tai-Kadai and Austroasiatic languages across Southeast and South Asia and mixing with the people they encountered, contributing to a four-fold reduction of genetic differentiation during the emergence of complex societies. We finally report data from Jomon hunter-gatherers from Japan who harbored one of the earliest splitting branches of East Eurasian variation, and show an affinity among Jomon, Amur River Basin, ancient Taiwan, and Austronesian-speakers, as expected for ancestry if they all had contributions from a Late Pleistocene coastal route migration to East Asia.

WOS:000577218500005 PubMed ID: 32963319 Oculocutaneous Albinism type 2 (OCA2) is a gene of great interest because of genetic variation affecting normal pigmentation variation in humans. The diverse geographic patterns for variant frequencies at OCA2 have been evident but have not been systematically investigated, especially outside of Europe. Here we examine population genetic variation in and near the OCA2 gene from a worldwide perspective. The very different patterns of genetic variation found across world regions suggest strong selection effects may have been at work over time. For example, analyses involving the variants that affect pigmentation of the iris argue that the derived allele of the rs1800407 single nucleotide polymorphism, which produces a hypomorphic protein, may have contributed to the previously demonstrated positive selection in Europe for the enhancer variant responsible for light eye color. More study is needed on the relationships of the genetic variation at OCA2 to variation in pigmentation in areas beyond Europe. NIJ Grants - National Institute of Justice, Office of Justice Programs, U.S. Department of Justice [2018-75-CX-0041, 2015-DN-BX-K023, 2016-DN-BX-0162, 2014-DN-BX-K030] The assembly and data analyses were funded primarily by NIJ Grants 2018-75-CX-0041, 2015-DN-BX-K023, 2016-DN-BX-0162, and 2014-DN-BX-K030 to KKK awarded by the National Institute of Justice, Office of Justice Programs, U.S. Department of Justice. Points of view in this presentation are those of the authors and do not necessarily represent the official position or policies of the U.S. Department of Justice. The authors thank Dr. Francoise R. Friedlaender for her expert help in creating Figs. 1, 2, 3 and 4. We would like to acknowledge all of our collaborators who helped collect the samples used in this research as well as the National Laboratory for the Genetics of Israeli Populations at Tel Aviv University and the Coriell Cell Repositories. Special thanks are due to the many hundreds of individuals who volunteered to give blood or saliva samples for studies of gene frequency variation.

Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In this study, we performed a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC. Experimental Design: GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls. Results: We identified a novel association signal within the CDK14 gene at 7q21.13 (index rs10272859, OR = 1.28, P = 9.46 × 10−10). Furthermore, we observed that the at-risk rs10272859[G] allele was significantly associated with higher mRNA expression levels of CDK14 in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of CDK14 and the risk-associated SNPs in strong linkage disequilibrium with the index rs10272859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients. Conclusions: Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the CDK14 gene to be the functional target of the 7q21.13 locus. Clin Cancer Res; 24(4); 906–15. ©2017 AACR.

Two rhodamine-based probes were designed and prepared, which exhibited highly sensitive and selective fluorescence enhancement upon binding to Pd 2+ by UV–vis and fluorescence spectroscopies. Meanwhile the distinct color changes and rapid switch-on fluorescence also provided “naked-eyes” detection for Pd 2+ over a broad pH range. The recognition mechanism was explored through Job’s plot, MS data, IR spectra and related theoretical calculations. Furthermore, the probes were applied for biological imaging to confirm that they can be used for monitoring Pd 2+ in living cells (L929 and A549 cells) and living mice with satisfying results, which further demonstrated their value of practical applications in environmental and biological systems.

High altitude polycythemia (HAPC) is a common chronic disease at high altitude, which is characterized by excessive erythrocytosis (females, hemoglobin ≥ 190 g/L; males, hemoglobin ≥ 210 g/L). It is the most common disease in chronic mountain sickness casued primarily by persistent arterial hypoxia and ventilatory impairment. However, the disease is still unmanageable and related molecular mechanisms remain largely unclear. This study aims to explore the genetic basis of HAPC in the Chinese Han and Tibetan populations. Subjects were screened for HAPC using the latest approved diagnostic criteria. To explore the hereditary basis of HAPC and investigate the association between three genes (EPAS1, ITGA6, ERBB4) and HAPC in Chinese Han and Tibetan populations. We enrolled 100 patients (70 Han, 30 Tibetan) with HAPC and 100 healthy control subjects (30 Han, 70 Tibetan). Subjects were screened for HAPC using the latest approved diagnostic criteria combined with excessive erythrocytosis and clinical symptoms. Analysis of variance was used to evaluate the impact of polymorphism on HAPC based on genetic variation. The Chi-squared test and analyses of genetic models, rs75591953 and rs75984373 in EPAS1, rs6744873 in ITGA6, rs17335043 in ERBB4 showed associations with reduced HAPC susceptibility in Han populations. Additionally, in Tibetan populations, rs3749148 in ITGA6, rs934607 and rs141267844 in ERBB4 showed a reduced risk of HAPC, whereas rs6710946 in ERBB4 increased the risk of HAPC. Our study suggest that the polymorphisms in the EPAS1, ITGA6 and ERBB4 correlate with susceptibility to HAPC.

High altitude polycythemia (HAPC) refers to the long-term living in the plateau of the hypoxia environment is not accustomed to cause red blood cell hyperplasia. The pathological changes are mainly the various organs and tissue congestion, blood stasis and hypoxia damage. Although chronic hypoxia is the main cause of HAPC, the related molecular mechanisms remain largely unclear. This study aims to explore the genetic basis of HAPC in the Chinese Han and Tibetan populations. We enrolled 100 patients (70 Han, 30 Tibetan) with HAPC and 100 healthy control subjects (30 Han, 70 Tibetan). To explore the hereditary basis of HAPC and investigate the association between EPHA2 with AGT and HAPC in Chinese Han and Tibetan populations. Using the Chi-squared test and analyses of genetic models, rs2291804, rs2291805, rs3768294, rs3754334, rs6603856, rs6669624, rs11260742, rs13375644 and rs10907223 in EPHA2, and rs699, rs4762 and rs5051 in AGT showed associations with reduced HAPC susceptibility in Han populations. Additionally, in Tibetan populations, rs2478523 in AGT showed an increased the risk of HAPC. Our study suggest that polymorphisms in the EPHA2 and AGT correlate with susceptibility to HAPC in Chinese Han and Tibetan populations.

Background The genetic relationships reported by recent studies between Sherpas and Tibetans are controversial. To gain insights into the population history and the genetic basis of high-altitude adaptation of the two groups, we analyzed genome-wide data in 111 Sherpas (Tibet and Nepal) and 177 Tibetans (Tibet and Qinghai), together with available data from present-day human populations. Results Sherpas and Tibetans show considerable genetic differences and can be distinguished as two distinct groups, even though the divergence between them (~3200–11,300 years ago) is much later than that between Han Chinese and either of the two groups (~6200–16,000 years ago). Sub-population structures exist in both Sherpas and Tibetans, corresponding to geographical or linguistic groups. Differentiation of genetic variants between Sherpas and Tibetans associated with adaptation to either high-altitude or ultraviolet radiation were identified and validated by genotyping additional Sherpa and Tibetan samples. Conclusions Our analyses indicate that both Sherpas and Tibetans are admixed populations, but the findings do not support the previous hypothesis that Tibetans derive their ancestry from Sherpas and Han Chinese. Compared to Tibetans, Sherpas show higher levels of South Asian ancestry, while Tibetans show higher levels of East Asian and Central Asian/Siberian ancestry. We propose a new model to elucidate the differentiated demographic histories and local adaptations of Sherpas and Tibetans. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1242-y) contains supplementary material, which is available to authorized users.

// Xun Li 1, * , Tianbo Jin 2, 3, * , Mingxia Zhang 3 , Hua Yang 3 , Xuewen Huang 1 , Xiaobo Zhou 1 , Wenchao Huang 1 , Lipeng Qin 1 , Longli Kang 2 , Ming Fan 4 , Suzhi Li 1 1 Center of Altitude Disease, General Hospital of Tibet Military Area Command, Lhasa 850003, China 2 Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 3 School of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China 4 Department of Brain Protection and Plasticity, Institute of Basic Medical Sciences, Beijing 100850, China * These authors contributed equally to this work and are joint first authors Correspondence to: Ming Fan, email: fanming1973@126.com Suzhi Li, email: suzhilixizang@163.com Keywords: high-altitude pulmonary edema (HAPE), single nucleotide polymorphisms (SNPs), genome wide association analysis (GWAS), susceptibility gene Received: October 20, 2016 Accepted: February 27, 2017 Published: March 18, 2017 ABSTRACT A two-stage genome-wide association study (GWAS) was performed to identify and analyze genes and single nucleotide polymorphisms (SNPs) associated with high-altitude pulmonary edema (HAPE) in a Han Chinese patient population. In the first stage, DNA samples from 68 patients with recurrent HAPE were scanned using Affymetrix SNP Array 6.0 Chips, and allele frequencies were compared to those of 84 HapMap CHB samples to identify candidate SNPs. In the second stage, the 77 identified candidate SNPs were examined in an independent cohort of samples from 199 HAPE patients and 304 controls. Associations between SNPs and HAPE risk were tested using various genetic models. Of the 77 original SNPs, 7 were found to be associated with HAPE susceptibility in the second stage of the study. GO and pathway enrichment analysis of the 7 SNPs revealed 5 adjacent genes involved in various processes, including regulation of nucleoside diphosphate metabolism, thyroid hormone catabolism, and low-density lipoprotein receptor activity. These results suggest the identified SNPs and genes may contribute to the physiopathology of HAPE.

// Yongjun He 1, 2, 3, * , Lijun Liu 1, 2, 3, * , Pengcheng Xu 4 , Na He 1, 2, 3 , Dongya Yuan 1, 2, 3 , Longli Kang 1, 2, 3 , Tianbo Jin 1, 2, 3 1 Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 2 Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 3 Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 4 Department of Hand Surgery, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, Hebei 061001, China * These authors have contributed equally to this work Correspondence to: Tianbo Jin, email: jintianbo@gmail.com Keywords: GNB3 , GSTP1 , ADRB2 , high-altitude pulmonary edema, genetic Received: August 12, 2016 Accepted: December 07, 2016 Published: February 14, 2017 ABSTRACT High altitude pulmonary edema (HAPE) occurs mainly under conditions such as high altitude, rapid ascent, or hypoxia. Previous studies suggest that ADRB2 , GNB3 , TH, and GSTP1 polymorphisms are associated with various lung diseases. We evaluated whether those polymorphisms are associated with the risk of HAPE in a Chinese Han population. ADRB2 , GNB3 , TH and GSTP1 polymorphisms were genotyped using a Sequenom MassARRAY. Logistic regression, adjusted for age and gender, was used to evaluate the association between the genotypes and the risk of HAPE by computing odds ratios (ORs) and 95% confidence intervals (95% CIs). The results revealed that GNB3 rs4963516 allele ‘‘G’’ (G vs T: OR = 0.70, 95% CI = 0.55–0.90, p = 0.006) was associated with HAPE risk. The ADRB2 rs1042718 alleles had a 1.29-fold (95%CI = 1.00-1.66; p = 0.045) increased risk of HAPE, and the GSTP1 rs749174 alleles had a 0.71-fold (95%CI = 0.52-0.99; p = 0.042) decreased risk of HAPE. Co-dominant and dominant models of GNB3 rs4963516 decreased the risk of HAPE ( p = 0.023 and p = 0.008, respectively). Our results indicate GNB3 and GSTP1 polymorphisms may protect against HAPE progression, while ADRB2 polymorphisms are associated with an increased risk of HAPE.

// Lijun Liu 1, 2, 3 , Jingjie Li 4 , Mengdan Yan 4 , Jing Li 4 , Junyu Chen 5 , Yi Zhang 5 , Xikai Zhu 1, 2, 3 , Li Wang 1, 2, 3 , Longli Kang 1, 2, 3 , Dongya Yuan 1, 2, 3 , Tianbo Jin 1, 2, 3, 4 1 Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 2 Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 3 Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 4 Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China 5 Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010050, China Correspondence to: Dongya Yuan, email: dongyayuanxzmz@gmail.com Tianbo Jin, email: jintianbo@gmail.com Keywords: TCF7L2 , schizophrenia, SNP, case-control Received: September 06, 2016 Accepted: January 04, 2017 Published: February 22, 2017 ABSTRACT Single nucleotide polymorphisms (SNPs) in TCF7L2 (Transcription Factor 7-Like 2) reportedly affect susceptibility to schizophrenia (SCZ). We examined the association between TCF7L2 polymorphisms and SCZ susceptibility in a Chinese Han population. Six SNPs were genotyped in 499 SCZ patients and 500 healthy individuals, after which their associations with SCZ were evaluated using the Chi-squared test and genetic model analyses. We observed that the allele A of rs12573128 is associated with an increased SCZ risk (odds ratio [OR] = 1.33, 95% confidence interval [CI]: 1.08-1.63, P = 0.006, adjusted P = 0.030). The AA genotype of rs12573128 was associated with a higher SCZ risk than the GG genotype, before and after adjustment for sex and age (adjusted OR = 2.97, 95% CI: 1.49-5.92, P = 0.002). In addition, SNP rs12573128 was associated with 1.47-fold, 2.64-fold and 1.50-fold increases in SCZ risk of in dominant, recessive and additive model, respectively (adjusted OR = 1.47, 95% CI = 1.09-1.99, P = 0.012; Bonferroni adjusted P = 0.030). adjusted OR = 2.64, 95% CI = 1.34-5.18, P = 0.005 and adjusted OR = 1.50, 95% CI = 1.17-1.93, P = 0.002, respectively). These results suggest rs12573128 is significantly associated with an increased risk of SCZ in the Chinese Han population.

The cytochrome P450 (CYP) 1A2 gene is involved in the metabolism of several carcinogens and clinically important drugs, generating a high potential for pharmacokinetic interactions. Since no data are available for Tibetan aborigines, the present study aimed to investigate the distribution of variant CYP1A2 alleles in a population living in Tibetan region of China. Genotyping analyses of CYP1A2 were conducted in 96 unrelated, healthy volunteers of Tibetan ancestry using direct sequencing assays. A total of 14 different CYP1A2 polymorphisms, including two novel variants (1690G>A and 2896C>T) in the intron region and a novel non-synonymous one (795G>C, Gln265His) were detected. CYP1A2*1A (6.77%), CYP1A2*1B (58.33%) and CYP1A2*1F (14.58%) were the most frequent defective alleles identified in the sample. The frequencies of the prevalent genotypes CYP1A2*1A/*1B, *1B/*1B, *1B/*1F were 13.54%, 16.67% and 29.17%, respectively. In addition, the novel non-synonymous variant 795G>C (Gln265His) was predicted to be benign by PolyPhen-2 and SIFT tools. The present study provides useful information on the pattern of CYP1A2 polymorphisms in Chinese Tibetan population. The current results may have potential benefits for the development of personalized medicine in the Tibetan population.

// Xue He 1, 2, 3, * , Xikai Zhu 1, 2, 3, * , Lei Li 4, 5 , Jiayi Zhang 6 , Ruipeng Wu 1, 2, 3 , Yuan Zhang 1, 2, 3 , Longli Kang 1, 2, 3 , Dongya Yuan 1, 2, 3 , Tianbo Jin 1, 2, 3, 6 1 Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 2 Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 3 Key Laboratory of High Altitude Environment and Gene Related to Disease of Tibet Ministry of Education, School of Medicine, Xizang Minzu University, Xianyang 712082, Shaanxi, China 4 Department of Thoracolumbar Spine Surgery, Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010000, China 5 Inner Mongolia Medical University, Hohhot, Inner Mongolia 010050, China 6 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an 710069, China * joint first authors Correspondence to: Tianbo Jin, email: jintianbo@gmail.com Dongya Yuan, email: dyyuanxzmz@gmail.com Keywords: astrocytoma, prognosis, overall survival, single nucleotide polymorphism Received: May 30, 2016 Accepted: October 26, 2016 Published: November 11, 2016 ABSTRACT Background: Gliomas are highly malignant with a poor prognosis. Studies have reported that DNA repair genes influence risk for glioma, but its relationship with prognosis is unclear. In this study, we want to explore the relationship between DNA repair genes ( XRCC3 , XRCC4 and XRCC5 ) and prognosis of astrocytoma in the Chinese Han population. Materials and Methods: 160 astrocytoma cases were recruited in our study. Survival probabilities were estimated by using Kaplan–Meier analysis, and significant differences were analyzed by using the log-rank test. Cox proportional hazards models were used to analyze the associations between genotypes with astrocytoma survival. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable models. All tests were two-sided and p < 0.05 was considered to be significant. Results: The SNP (rs9288516) in XRCC5 (HR: 1.69, 95%CI: 1.04 - 2.77, p = 0.049), surgical approach (HR: 0.61, 95%CI: 0.43 - 0.88, p = 0.003) and chemotherapy (HR: 0.71, 95%CI: 0.50 - 0.99, p = 0.029) were associated with astrocytoma prognosis. Further, the “A/A” genotype of rs9288516 in XRCC5 (HR: 1.67, 95%CI: 1.02 - 2.72, p = 0.042) had significantly outcomes after adjusting for potential confounders, patients with poor tumor differentiation and the coexistence of the unfavorable genotypes. Conclusion: These results suggest that polymorphisms of XRCC5 play an important role in astrocytoma prognosis in the Chinese Han population which could be used in the determination of astrocytoma prognosis in clinical researches.

A special fluorescent probe has been developed, one that demonstrated excellent "off-on-type" change in fluorescence with high selectivity toward Cu

The origin of Tibetans remains one of the most contentious puzzles in history, anthropology, and genetics. Analyses of deeply sequenced (30×–60×) genomes of 38 Tibetan highlanders and 39 Han Chinese lowlanders, together with available data on archaic and modern humans, allow us to comprehensively characterize the ancestral makeup of Tibetans and uncover their origins. Non-modern human sequences compose ∼6% of the Tibetan gene pool and form unique haplotypes in some genomic regions, where Denisovan-like, Neanderthal-like, ancient-Siberian-like, and unknown ancestries are entangled and elevated. The shared ancestry of Tibetan-enriched sequences dates back to ∼62,000–38,000 years ago, predating the Last Glacial Maximum (LGM) and representing early colonization of the plateau. Nonetheless, most of the Tibetan gene pool is of modern human origin and diverged from that of Han Chinese ∼15,000 to ∼9,000 years ago, which can be largely attributed to post-LGM arrivals. Analysis of ∼200 contemporary populations showed that Tibetans share ancestry with populations from East Asia (∼82%), Central Asia and Siberia (∼11%), South Asia (∼6%), and western Eurasia and Oceania (∼1%). Our results support that Tibetans arose from a mixture of multiple ancestral gene pools but that their origins are much more complicated and ancient than previously suspected. We provide compelling evidence of the co-existence of Paleolithic and Neolithic ancestries in the Tibetan gene pool, indicating a genetic continuity between pre-historical highland-foragers and present-day Tibetans. In particular, highly differentiated sequences harbored in highlanders’ genomes were most likely inherited from pre-LGM settlers of multiple ancestral origins (SUNDer) and maintained in high frequency by natural selection.

Introduction High altitude pulmonary edema (HAPE) is a kind of pneumonedema that mostly occurs for the conditions like high altitude, rapid ascent, hypoxia and so on. Previous study suggested that ACYP2 polymorphism was associated with mean telomere length, and telomere length were significantly longer in the moderate attitude than the sea-level or simulate high attitude. Aims The aim of this study was to identify if there is any association between ACYP2 polymorphism and the risk of HAPE. Results Through Chi-square tests, we found that the minor allele G of rs11896604 is significantly associated with a decreased risk of HAPE (OR = 0.87, 95%CI = 0.65-1.16, p = 0.048). We also found that the ‘A/A’ genotype of rs12615793 is associated with decreased HAPE risk based on the recessive model (OR = 0.28; 95% CI = 0.09-0.88; p = 0.017). Additionally, the ‘G/G’ genotype of rs11896604 was found to be associated with decreased HAPE risk based on the codominant model (OR = 0.26; 95% CI = 0.08-0.79; p = 0.025) and recessive model (OR = 0.25; 95% CI = 0.08-0.77; p = 0.007). However, only rs11896604 remained significant after Bonferroni correction (p

Variants of the cleft lip and palate trans-membrane 1 like (CLPTM1L) gene, located on chromosome 5p15.33, were previously determined to influence lung cancer susceptibility. Here, we performed a case-control study to examine the potential association of CLPTM1L single nucleotide polymorphisms (SNPs) with lung cancer in a Chinese Han population. We selected four SNPs in the CLPTM1L gene that were previously reported to be associated with lung cancer. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to estimate the strength of the relationship between each CLPTM1L SNP and lung cancer risk. Allelic model analysis revealed that the minor alleles of all four SNPs were significantly associated with decreased lung cancer risk. Similar significant results were detected using genetic model analysis. In addition, we observed a protective effect of haplotype "TT" in the CLPTM1L gene. Our results verified that certain CLPTM1L polymorphisms are protective factors against lung cancer in a southern Chinese Han population and may be potential diagnostic and molecular markers for lung cancer patients.