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Abstract Evidence for adaptation of human skin color to regional ultraviolet radiation suggests shared and distinct genetic variants across populations. However, skin color evolution and genetics in East Asians are understudied. We quantified skin color in 48,433 East Asians using image analysis and identified associated genetic variants and potential causal genes for skin color as well as their polygenic interplay with sun exposure. This genome-wide association study (GWAS) identified 12 known and 11 previously unreported loci and SNP-based heritability was 23–24%. Potential causal genes were determined through the identification of nonsynonymous variants, colocalization with gene expression in skin tissues, and expression levels in melanocytes. Genomic loci associated with pigmentation in East Asians substantially diverged from European populations, and we detected signatures of polygenic adaptation. This large GWAS for objectively quantified skin color in an East Asian population improves understanding of the genetic architecture and polygenic adaptation of skin color and prioritizes potential causal genes.

Abstract Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.

Angiogenesis is an indispensable mechanism in cancer progression, as cancer cells need to establish blood vessels to supply oxygen and nutrients. Extracellular vesicles (EVs) derived from cancer cells act as messengers in the tumor microenvironment and induce resistance to anti-angiogenic cancer treatment. EVs can be classified into two categories: exosomes and microvesicles (MVs). Although exosomes are involved in angiogenesis, the role of MVs in angiogenesis and cancer progression remains unclear. CD133 plays a key role in MV formation and oncoprotein trafficking. In this study, we investigated the role of CD133-containing MVs derived from colorectal cancer (CRC) in angiogenesis and cancer progression. CRC-derived MVs were incorporated into endothelial cells and increased the mesh area and tube length of endothelial cells. CD133-containing MVs also stimulate vessel sprouting in endothelial cell spheroids and mouse thoracic aortas. However, MVs derived from CD133-knockdown CRC cells exerted a limited effect on tube formation and vessel sprouting. CD133-containing MVs induced angiogenesis through p38 activation and angiogenesis induced by CD133-containing MVs was insensitive to the anti-vascular endothelial growth factor antibody bevacizumab. Survival analysis revealed that high expression level of CD133 correlated with poor prognosis in patients with metastatic CRC. These findings suggest that CD133-containing MVs act as key regulators of angiogenesis and are related to the prognosis of CRC patients.

Abstract Irritability is a heritable core mental trait associated with several psychiatric illnesses. However, the genomic basis of irritability is unclear. Therefore, this study aimed to 1) identify the genetic variants associated with irritability and investigate the associated biological pathways, genes, and tissues as well as single-nucleotide polymorphism (SNP)-based heritability; 2) explore the relationships between irritability and various traits, including psychiatric disorders; and 3) identify additional and shared genetic variants for irritability and psychiatric disorders. We conducted a genome-wide association study (GWAS) using 379,506 European samples (105,975 cases and 273,531 controls) from the UK Biobank. We utilized various post-GWAS analyses, including linkage disequilibrium score regression, the bivariate causal mixture model (MiXeR), and conditional and conjunctional false discovery rate approaches. This GWAS identified 15 independent loci associated with irritability; the total SNP heritability estimate was 4.19%. Genetic correlations with psychiatric disorders were most pronounced for major depressive disorder (MDD) and bipolar II disorder (BD II). MiXeR analysis revealed polygenic overlap with schizophrenia (SCZ), bipolar I disorder (BD I), and MDD. Conditional false discovery rate analyses identified additional loci associated with SCZ (number [n] of additional SNPs = 105), BD I (n = 54), MDD (n = 107), and irritability (n = 157). Conjunctional false discovery rate analyses identified 85, 41, and 198 shared loci between irritability and SCZ, BD I, and MDD, respectively. Multiple genetic loci were associated with irritability and three main psychiatric disorders. Given that irritability is a cross-disorder trait, these findings may help to elucidate the genomics of psychiatric disorders.

Fusion devices like tokamaks require plasma current to generate magnetic field for plasma confinement. Here the authors report an observation of a self-generated anomalous current that contributes up to 30% of the total current in the fusion plasma at KSTAR.

BackgroundThe genetic basis of amyloid β (Aβ) deposition in subcortical vascular cognitive impairment (SVCI) is still unknown. Here, we investigated genetic variants involved in Aβ deposition in patients with SVCI.MethodsWe recruited a total of 110 patients with SVCI and 424 patients with Alzheimer’s disease-related cognitive impairment (ADCI), who underwent Aβ positron emission tomography and genetic testing. Using candidate AD-associated single nucleotide polymorphisms (SNPs) that were previously identified, we investigated Aβ-associated SNPs that were shared or distinct between patients with SVCI and those with ADCI. Replication analyses were performed using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Rush Memory and Aging Project cohorts (ROS/MAP).ResultsWe identified a novel SNP, rs4732728, which showed distinct associations with Aβ positivity in patients with SVCI (Pinteraction = 1.49 × 10–5); rs4732728 was associated with increased Aβ positivity in SVCI but decreased Aβ positivity in ADCI. This pattern was also observed in ADNI and ROS/MAP cohorts. Prediction performance for Aβ positivity in patients with SVCI increased (area under the receiver operating characteristic curve = 0.780; 95% confidence interval = 0.757–0.803) when rs4732728 was included. Cis-expression quantitative trait loci analysis demonstrated that rs4732728 was associated with EPHX2 expression in the brain (normalized effect size = −0.182, P = 0.005).ConclusionThe novel genetic variants associated with EPHX2 showed a distinct effect on Aβ deposition between SVCI and ADCI. This finding may provide a potential pre-screening marker for Aβ positivity and a candidate therapeutic target for SVCI.

Panax ginseng C.A. Meyer, a widely used traditional medicine in East Asia, shows many beneficial effects on immune function, male erectile dysfunction, cancer, excessive oxidants, and aging issues. However, its effect on benign prostatic hyperplasia (BPH) and its potential in the treatment of side effects related to finasteride (Fi), an FDA-approved drug for BPH, are less known. This study aimed to verify the therapeutic effects of a water extract of P. ginseng (PGWE) on BPH in testosterone propionate (TP)-induced BPH rats and TP-treated RWPE-1 human epithelial cells, and the inhibitory potential on the Fi-induced side effects is also explored. In the TP-induced BPH rat model, PGWE alleviated the pathological markers of BPH such as weight and epithelial thickness of the prostate, and the serum level of dihydrotestosterone. PGWE downregulated androgen-related BPH factors such as 5α-reductase 2 and androgen receptor. PGWE also showed prostatic cell apoptosis accompanied by increased expression of Bax and decreased expression of Bcl-xL and cleaved-caspase 3, respectively, in addition to increasing mitochondrial dynamics in both in vivo and in vitro BPH models. Notably, reduced sperm count, one of the serious side effects of Fi, in the epididymis of BPH rats was recovered with PGWE treatment, suggesting less toxicity to sperm development by PGWE. PGWE also protected against Fi-induced sperm loss when PGWE was administered in combination with Fi without compromising the therapeutic effects of Fi on BPH. Based on these findings, we propose that PGWE could be an alternative therapeutic agent for BPH.

Abstract Background Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer’s disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid β (Aβ) positivity using a large sample of Korean population. Methods One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aβ positivity (measured by amyloid positron emission tomography). Aβ prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. Results In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aβ positivity (p

Obesity is a burden to global health. Non-shivering thermogenesis of brown adipose tissue (BAT) and white adipose tissue (WAT) is a novel strategy for obesity treatment. Anmyungambi (AMGB) decoction is a multi-herb decoction with clinical anti-obesity effects. Here, we show the effects of AMGB decoction using high-fat diet (HFD)-fed C57BL6/J mice. All four versions of AMGB decoction (100 mg/kg/day, oral gavage for 28 days) suppressed body weight gain and obesity-related blood parameters in the HFD-fed obese mice. They also inhibited adipogenesis and induced lipolysis in inguinal WAT (iWAT). Especially, the AMGB-4 with 2:1:3:3 composition was the most effective; thus, further studies were performed with the AMGB-4 decoction. The AMGB-4 decoction displayed a dose-dependent body weight gain suppression. Serum triglyceride, total cholesterol, and blood glucose decreased as well. In epididymal WAT, iWAT, and BAT, the AMGB-4 decoction increased lipolysis markers. Additionally, the AMGB-4 decoction-fed mice showed an increased non-shivering thermogenic program in BAT and iWAT. Excessive reactive oxygen species (ROS) and suppressed antioxidative factors induced by the HFD feeding were also altered to normal levels by the AMGB-4 decoction treatment. Overall, our study supports the clinical use of AMGB decoction for obesity treatment by studying its mechanisms. AMGB decoction alleviates obesity through the activation of the lipolysis–thermogenesis program and the elimination of pathological ROS in thermogenic adipose tissues.