Biomarkers for systemic lupus erythematosus: A scoping review.

BACKGROUND: In recent years, newly discovered potential biomarkers have great research potential in the diagnosis, disease activity prediction, and treatment of systemic lupus erythematosus (SLE). OBJECTIVE: In this study, a scoping review of potential biomarkers for SLE over several years has identified the extent to which studies on biomarkers for SLE have been conducted, the specificity, sensitivity, and diagnostic value of potential biomarkers of SLE, the research potential of these biomarkers in disease diagnosis, and activity detection is discussed. METHODS: In PubMed and Google Scholar databases, "SLE," "biomarkers," "predictor," "autoimmune diseases," "lupus nephritis," "neuropsychiatric SLE," "diagnosis," "monitoring," and "disease activity" were used as keywords to systematically search for SLE molecular biomarkers published from 2020 to 2024. Analyze and summarize the literature that can guide the article. CONCLUSIONS: Recent findings suggest that some potential biomarkers may have clinical application prospects. However, to date, many of these biomarkers have not been subjected to repeated clinical validation. And no single biomarker has sufficient sensitivity and specificity for SLE. It is not scientific to choose only one or several biomarkers to judge the complex disease of SLE. It may be a good direction to carry out a meta-analysis of various biomarkers to find SLE biomarkers suitable for clinical use, or to evaluate SLE by combining multiple biomarkers through mathematical models. At the same time, advanced computational methods are needed to analyze large data sets and discover new biomarkers, and strive to find biomarkers that are sensitive and specific enough to SLE and can be used in clinical practice, rather than only staying in experimental research and data analysis.

NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors.

To identify novel susceptibility genes for hepatocellular carcinoma (HCC), we performed a rare-variant association study in Chinese populations consisting of 2,750 cases and 4,153 controls. We identified four HCC-associated genes, including NRDE2, RANBP17, RTEL1, and STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10-9) as an exemplary candidate, we demonstrated that it promotes homologous recombination (HR) repair and suppresses HCC. Mechanistically, NRDE2 binds to the subunits of casein kinase 2 (CK2) and facilitates the assembly and activity of the CK2 holoenzyme. This NRDE2-mediated enhancement of CK2 activity increases the phosphorylation of MDC1 and then facilitates the HR repair. These functions are eliminated almost completely by the NRDE2-p.N377I variant, which sensitizes the HCC cells to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight the relevance of the rare variants to genetic susceptibility to HCC, which would be helpful for the precise treatment of this malignancy.

A novel risk variant block across introns 36-45 of CACNA1C for schizophrenia: a cohort-wise replication and cerebral region-wide validation study.

OBJECTIVES: Numerous genome-wide association studies have identified CACNA1C as one of the top risk genes for schizophrenia. As a necessary post-genome-wide association study (GWAS) follow-up, here, we focused on this risk gene, carefully investigated its novel risk variants for schizophrenia, and explored their potential functions. METHODS: We analyzed four independent samples (including three European and one African-American) comprising 5648 cases and 6936 healthy subjects to identify replicable single nucleotide polymorphism-schizophrenia associations. The potential regulatory effects of schizophrenia-risk alleles on CACNA1C mRNA expression in 16 brain regions (n = 348), gray matter volumes (GMVs) of five subcortical structures (n = 34 431), and surface areas and thickness of 34 cortical regions (n = 36 936) were also examined. RESULTS: A novel 17-variant block across introns 36-45 of CACNA1C was significantly associated with schizophrenia in the same effect direction across at least two independent samples (1.8 × 10-4 ≤ P ≤ 0.049). Most risk variants within this block showed significant associations with CACNA1C mRNA expression (1.6 × 10-3 ≤ P ≤ 0.050), GMVs of subcortical structures (0.016 ≤ P ≤ 0.048), cortical surface areas (0.010 ≤ P ≤ 0.050), and thickness (0.004 ≤ P ≤ 0.050) in multiple brain regions. CONCLUSION: We have identified a novel and functional risk variant block at CACNA1C for schizophrenia, providing further evidence for the important role of this gene in the pathogenesis of schizophrenia.

Genetic Origins and Adaptive Evolution of the Deng People on the Tibetan Plateau.

The Tibetan Plateau is populated by diverse ethnic groups, but most of them are underrepresented in genomics studies compared with the Tibetans (TIB). Here, to gain further insight into the genetic diversity and evolutionary history of the people living in the Tibetan Plateau, we sequenced 54 whole genomes of the Deng people with high coverage (30-60×) and analyzed the data together with that of TIB and Sherpas, as well as 968 ancient Asian genomes and available archaic and modern human data. We identified 17.74 million novel single-nucleotide variants from the newly sequenced genomes, although the Deng people showed reduced genomic diversity and a relatively small effective population size. Compared with the other Tibetan highlander groups which are highly admixed, the Deng people are dominated by a sole ancestry that could be traced to some ancient northern East Asian populations. The divergence between Deng and Tibetan people (∼4,700-7,200 years) was more recent than that between highlanders and the Han Chinese (Deng-HAN, ∼9,000-14,000 years; TIB-HAN, 7,200-10,000 years). Adaptive genetic variants (AGVs) identified in the Deng are only partially shared with those previously reported in the TIB like HLA-DQB1, whereas others like KLHL12 were not reported in TIB. In contrast, the top candidate genes harboring AGVs as previously identified in TIB, like EPAS1 and EGLN1, do not show strong positive selection signals in Deng. Interestingly, Deng also showed a different archaic introgression scenario from that observed in the TIB. Our results suggest that convergent adaptation might be prevalent on the Tibetan Plateau.

Changes in expression levels of erythrocyte and immune-related genes are associated with high altitude polycythemia.

BACKGROUND: As a chronic mountain sickness(CMS) with the highest incidence and the greatest harm, the pathogenesis of high altitude polycythemia (HAPC) is still not fully understood. METHODS: 37 HAPC patients and 42 healthy subjects were selected from plateau, and peripheral venous blood samples were collected for transcriptome sequencing on Illumina NovaSeq platform. The sequenced data were analyzed by bioinformatics and phenotypic association analysis. RESULTS: The results showed significant differences in multiple clinical indicators including RBC and HGB et al. existed between HAPC and control. Based on the RNA-seq data, 550 genes with significant differential expression were identified in HAPC patients. GO and KEGG pathway enrichment analysis showed that the up-regulated genes were mainly enriched in processes such as erythrocyte differentiation and development and homeostasis of number of cells, while the down-regulated genes were mainly enriched in categories such as immunoglobulin production, classical pathway of complement activation and other biological processes. The coupling analysis of differential expression genes(DEGs) and pathological phenotypes revealed that 91 DEGs were in close correlation with in the phenotype of red blood cell volume distribution (width-CV and width-SD), and they were all up-regulated in HAPC and involved in the process of erythrocyte metabolism. Combined with the functional annotation of DEGs and literature survey, we found that the expression of several potential genes might be responsible for pathogenesis of HAPC. Besides, cell type deconvolution analysis result suggested that the changes in the number of some immune cell types was significantly lower in HAPC patients than control, implying the autoimmune level of HAPC patients was affected to a certain extent. CONCLUSION: This study provides an important data source for understanding the pathogenesis and screening pathogenic genes of HAPC. We found for the first time that there was a significant correlation between HAPC and the pathological phenotype of width-CV and width-SD, wherein the enriched genes were all up-regulated expressed and involved in the process of erythrocyte metabolism. Although the role of these genes needs to be further studied, the candidate genes can provide a starting point for functionally pinning down the underlying mechanism of HAPC.

Gut microbiome alterations in pulmonary hypertension in highlanders and lowlanders.

Background: Alterations in the gut microbiota have been observed in patients with pulmonary hypertension (PH), though whether the roles of the gut microbiota in PH at different altitudes are the same is unknown. This study aims to evaluate the associations of the gut microbiome with PH in highlanders and lowlanders. Methods: PH patients and controls were recruited from those who permanently live on the Tibetan plateau (highlanders) or the plains (lowlanders), and underwent transthoracic echocardiography close to their altitude of residence (at 5070 m for highlanders versus6 m for lowlanders). The gut microbiome was profiled using metagenomic shotgun sequencing. Results: In total, 13 PH patients (46% highlanders) and 88 controls (70% highlanders) were included. The overall microbial composition was different in PH patients compared to controls (p=0.003). Notably, among lowlanders, a composite microbial score of pro-atherosclerotic trimethylamine-producing species was increased in PH patients compared with that in controls (p=0.028), while among highlanders no such difference was observed (p=0.087). Another composite gut microbial score including eight species of Lactobacillus, which has shown beneficial effects on cardiovascular functions, was higher in highlanders than lowlanders (p<0.01). Furthermore, this score tended to be lower in PH patients than controls among highlanders (p=0.056) but not among lowlanders (p=0.840). In addition, the gut microbiome showed a good performance in distinguishing PH patients from controls in both lowlanders and highlanders. Conclusions: Our study reported differently altered gut microbiome profiles between highland and lowland PH patients, highlighting the distinct microbial mechanism in PH in highlanders compared with lowlanders.

A significant, functional and replicable risk KTN1 variant block for schizophrenia.

Cortical and subcortical structural alteration has been extensively reported in schizophrenia, including the unusual expansion of gray matter volumes (GMVs) of basal ganglia (BG), especially putamen. Previous genome-wide association studies pinpointed kinectin 1 gene (KTN1) as the most significant gene regulating the GMV of putamen. In this study, the role of KTN1 variants in risk and pathogenesis of schizophrenia was explored. A dense set of SNPs (n = 849) covering entire KTN1 was analyzed in three independent European- or African-American samples (n = 6704) and one mixed European and Asian Psychiatric Genomics Consortium sample (n = 56,418 cases vs. 78,818 controls), to identify replicable SNP-schizophrenia associations. The regulatory effects of schizophrenia-associated variants on the KTN1 mRNA expression in 16 cortical or subcortical regions in two European cohorts (n = 138 and 210, respectively), the total intracranial volume (ICV) in 46 European cohorts (n = 18,713), the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258), and the surface areas (SA) and thickness (TH) of whole cortex and 34 cortical regions in 50 European cohorts (n = 33,992) and eight non-European cohorts (n = 2944) were carefully explored. We found that across entire KTN1, only 26 SNPs within the same block (r2 > 0.85) were associated with schizophrenia across ≥ 2 independent samples (7.5 × 10-5 ≤ p ≤ 0.048). The schizophrenia-risk alleles, which increased significantly risk for schizophrenia in Europeans (q < 0.05), were all minor alleles (f < 0.5), consistently increased (1) the KTN1 mRNA expression in 12 brain regions significantly (5.9 × 10-12 ≤ p ≤ 0.050; q < 0.05), (2) the ICV significantly (6.1 × 10-4 ≤ p ≤ 0.008; q < 0.05), (3) the SA of whole (9.6 × 10-3 ≤ p ≤ 0.047) and two regional cortices potentially (2.5 × 10-3 ≤ p ≤ 0.042; q > 0.05), and (4) the TH of eight regional cortices potentially (0.006 ≤ p ≤ 0.050; q > 0.05), and consistently decreased (1) the BG GMVs significantly (1.8 × 10-19 ≤ p ≤ 0.050; q < 0.05), especially putamen GMV (1.8 × 10-19 ≤ p ≤ 1.0 × 10-4; q < 0.05, (2) the SA of four regional cortices potentially (0.010 ≤ p ≤ 0.048), and (3) the TH of four regional cortices potentially (0.015 ≤ p ≤ 0.049) in Europeans. We concluded that we identified a significant, functional, and robust risk variant block covering entire KTN1 that might play a critical role in the risk and pathogenesis of schizophrenia.

Association Study Between Polymorphic Loci in Cholesterol Metabolism Pathway and Gallstone in the Tibetan Population.

Background: The incidence of gallstones in the Tibetan population is increasing rapidly. Previous studies indicated that genetic variation located in the cholesterol metabolism pathway may be associated with the incidence of gallstones. Methods: By recruiting 132 Tibetan gallstone patients and 52 normal Tibetan controls, we performed next-generation sequencing for 508 genes in the cholesterol metabolism pathway. Additionally, by integrating the sequence data of 41 normal Tibetan subjects in the public database, we finally obtained 93 normal Tibetan controls. Single nucleotide polymorphisms (SNPs) calling were performed by using the GATK pipeline. The quality control criteria for SNPs were: missing rate <0.05; minor allele frequency (MAF) > 0.01; and p value >0.001 in the Hardy-Weinberg Equilibrium (HWE) test. To eliminate the influence of population heterogeneity, Principal Component Analysis (PCA) was carried out by using the smartpca software. Association analyses were performed by Plink software. Multiple tests were adjusted by the false discovery rate (FDR) method. Results: A total of 2,401 SNPs were obtained by analyzing 508 genes, and 2,011 SNPs left after quality control. After adjusting the eigen vectors, we found that 10 SNPs (SNV05997, rs80145081, rs80005560, rs79074685, rs748546375, rs201880593, rs142559357, rs750769471, rs869789 and rs4072341) were significantly associated with gallstone. Subsequently, by comparing the case group with our control group and the public database control group separately, we further found that the SNP rs869789 was consistently significantly associated with gallstone (p = 9.04 × 10-3 in cases vs. our controls and 5.73 × 10-3 in cases vs. public controls, respectively). Conclusion: By systematically analyzed SNPs in the cholesterol metabolism pathway, we identified one polymorphic locus rs869789 significantly associated with the pathogenesis of gallstone in the Tibetan population. This study will provide clue for further mechanism study of gallstone in the Tibetan population.

Targeted Sequencing Identifies the Genetic Variants Associated with High-altitude Polycythemia in the Tibetan Population.

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. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-021-01474-1.

Smaller reaction volume of triplex taqman real-time reverse transcription-PCR assays for diagnosing coronavirus disease 2019.

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.

An independent, replicable, functional and significant risk variant block at intron 3 of CACNA1C for schizophrenia.

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.

Migration effects on the intestinal microbiota of Tibetans.

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.

Effects of Helicobacter pylori Infection on the Oral Microbiota of Reflux Esophagitis Patients.

The human oral microbiota plays a vital role in maintaining metabolic homeostasis. To explore the relationship between Helicobacter pylori (Hp) and reflux esophagitis, we collected 86 saliva samples from reflux esophagitis patients (RE group) and 106 saliva samples from healthy people (C group) for a high-throughput sequencing comparison. No difference in alpha diversity was detected between the RE and the C groups, but beta diversity of the RE group was higher than the C group. Bacteroidetes was more abundant in the RE group, whereas Firmicutes was more abundant in the C group. The linear discriminant analysis effect size analysis demonstrated that the biomarkers of the RE group were Prevotella, Veillonella, Leptotrichia, and Actinomyces, and the biomarkers of the C group were Lautropia, Gemella, Rothia, and Streptococcus. The oral microbial network structure of the C group was more complex than that of the RE group. Second, to explore the effect of Hp on the oral microbiota of RE patients, we performed the 14C-urea breath test on 45 of the 86 RE patients. We compared the oral microbiota of 33 Hp-infected reflux esophagitis patients (REHpp group) and 12 non-Hp-infected reflux esophagitis patients (REHpn group). No difference in alpha diversity was observed between the REHpn and REHpp groups, and beta diversity of the REHpp group was significantly lower than that of the REHpn group. The biomarkers in the REHpp group were Veillonella, Haemophilus, Selenomonas, Megasphaera, Oribacterium, Butyrivibrio, and Campylobacter; and the biomarker in the REHpn group was Stomatobaculum. Megasphaera was positively correlated with Veillonella in the microbial network of the REHpp group. The main finding of this study is that RE disturbs the human oral microbiota, such as increased beta diversity. Hp infection may inhibit this disorderly trend.

Effects of altitude on human oral microbes.

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 (< 3650 m) was 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.

Using Composite Phenotypes to Reveal Hidden Physiological Heterogeneity in High-Altitude Acclimatization in a Chinese Han Longitudinal Cohort.

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.

The distinctive geographic patterns of common pigmentation variants at the OCA2 gene.

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.

KTN1 Variants Underlying Putamen Gray Matter Volumes and Parkinson's Disease.

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 ≤ ß ≤ 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.

Replicated risk CACNA1C variants for major psychiatric disorders may serve as potential therapeutic targets for the shared depressive endophenotype.

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 (p<10-6) and replicated associations between risk SNPs and MPDs. We found the associations of 6 variants located in 6 genes, including L type voltage-gated calcium channel (LTCCs) subunit alpha1 C gene (CACNA1C), that were genome-wide significant (2.0×10 -8 ≤p≤1.0×10 -6 ) and replicated at single-point level across at least two GWASs. Among them, the associations between MPDs and rs1006737 within CACNA1C are most robust. Thus, as a next step, the expression of the replicated risk genes in human hippocampus was analyzed. We found CACNA1C had significant mRNA expression in human hippocampus in two independent cohorts. Finally, we tried to elucidate the roles of venlafaxine and ω-3 PUFAs in the mRNA expression regulation of the replicated risk genes in hippocampus. We used cDNA chip-based microarray profiling to explore the transcriptome-wide mRNA expression regulation by ω-3 PUFAs (0.72/kg/d) and venlafaxine (0.25/kg/d) treatment in chronic mild stress (CMS) rats. ω-3 PUFAs and venlafaxine treatment elicited significant CACNA1C up-regulation. We concluded that CACNA1C might confer the genetic vulnerability to the shared depressive symptoms across MPDs and CACNA1C might be the therapeutic target for depressive endophenotype as well.

The massive assimilation of indigenous East Asian populations in the origin of Muslim Hui people inferred from paternal Y chromosome.

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.