Validation of genome-wide association studies (GWAS)-identified type 2 diabetes mellitus risk variants in Pakistani Pashtun population / Journal of the ASEAN Federation of Endocrine Societies

Objective@#Recent GWAS largely conducted in European populations have successfully identified multiple genetic risk variants associated with Type 2 Diabetes Mellitus (T2DM). However, the effects conferred by these variants in the Pakistani population have not yet been fully elucidated. The objective of this study was to examine European GWAS- identified T2DM risk variants in the Pakistani Pashtun population to better understand the shared genetic basis of T2DM in the European and Pakistani cohorts.@*Methodology@#A total of 100 T2DM patients and 100 healthy volunteers of Pashtun ethnicity were enrolled in this study. Both groups were genotyped for 8 selected single nucleotide polymorphisms (SNPs) using the Sequenom MassARRAY® platform. The association between selected SNPs and T2DM was determined by using appropriate statistical tests.@*Results@#Of the 8 studied SNPs, 5 SNPs, SLC30A8/ rs13266634 (p=0.031, OR=2.13), IGF2BP2/ rs4402960 (p=0.001, OR=3.01), KCNJ11/ rs5219 (p=0.042, OR=1.78), PPARG/ rs1801282 (p=0.042, OR=2.81) and TCF7L2/ rs7903146 (p=0.00006, 3.41) had a significant association with T2DM. SNP GLIS3/ rs7041847 (p=0.051, OR=2.01) showed no sufficient evidence of association. SNPs KCNQ1/ rs2237892 (p=0.140, OR=1.61) and HHEX/IDE/ s1111875 (p=0.112, OR=1.31) showed opposite allelic effects and were not validated for T2DM risk in the study population. Among the studied SNPs, TCF7L2/ rs7903146 showed the most significant association.@*Conclusion@#Our study finding indicates that selected genome-wide significant T2DM risk variants previously identified in European descent also increase the risk of developing T2DM in the Pakistani Pashtun population.

Causal association between interleukin and constipation: A Mendelian randomization analysis / 西安交通大学学报(医学版)

【Objective】 To explore the causal association between interleukin (IL) level and constipation by using two-sample Mendelian randomization. 【Methods】 Analyses were performed based on the data from gene-wide association studies (GWAS). Both interleukin and constipation data were obtained from European populations. IL as an exposure variable was obtained from two GWAS data sets: ⅰ. from a genetic map of the human plasma proteome containing 3 301 samples; ⅱ. from a GWAS data set on 90 circulating proteins, containing 30 931 samples. Constipation as an outcome variable was obtained from two GWAS data sets: ⅰ. from Finngene, containing 26919 cases and 282235 controls; ⅱ. from UKBiobank, containing a total of 3 328 cases and 459682 controls. Single nucleotide polymorphisms strongly associated with exposure variables were used as instrumental variables, with inverse variance weighted (IVW) as the main analysis method, MR-egger regression and weighted median method as supplementary evidence for IVW results, and horizontal pleiotropy and heterogeneity were tested to ensure the stability of the results. 【Results】 In both of the two different outcome variables GWAS data, IVW analysis results showed that decreased level of IL-17 receptor C was associated with an increased risk of constipation, with ORs of 0.956 (95% CI: 0.916-0.997, P=0.036‖Finngene) and 0.998 (95% CI: 0.997-0.999, P=0.040‖ukb). Increased level of IL-18 was associated with an increased risk of constipation, with ORs of 1.055 (95% CI: 1.008-1.104, P=0.022‖Finngene) and 1.001 (95% CI: 1.000-1.002, P=0.044‖ukb); while in the Finngene data, the IVW results also suggested that increased levels of IL-2 receptor alpha subunit α and decreased levels of IL-10 and IL-17 were associated with an increased risk of constipation, with ORs of 1.054 (95% CI: 1.001-1.110, P=0.049), 0.945 (95% CI: 0.896-0.996, P=0.035) and 0.934 (95% CI: 0.896-0.997, P=0.040). 【Conclusion】 IL-17 receptor C, IL-18, IL-2 receptor alpha subunit α, IL-10, and IL-17 were causally associated with the risk of constipation.

Genome-wide analysis identify novel germline genetic variations in ADCY1 influencing platinum-based chemotherapy response in non-small cell lung cancer

To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P < 1 × 10-3 in cohort 1 discovery stage, of which 3 SNPs were verified in 262 independent samples. A total of 541 SNPs were significant at P < 1 × 10-4 in cohort 2 discovery stage, of which 8 SNPs were verified in 347 independent samples. Comparing the validated SNPs in two GWAS, ADCY1 gene was verified in both independent studies. The results of fine-mapping showed that the G allele carriers of ADCY1 rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy. In conclusion, our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.

Disentangling the genetic bases of Saccharomyces cerevisiae nitrogen consumption and adaptation to low nitrogen environments in wine fermentation

The budding yeast Saccharomyces cerevisiae has been considered for more than 20 years as a premier model organ- ism for biological sciences, also being the main microorganism used in wide industrial applications, like alcoholic fermentation in the winemaking process. Grape juice is a challenging environment for S. cerevisiae , with nitrogen deficiencies impairing fermentation rate and yeast biomass production, causing stuck or sluggish fermentations, thus generating sizeable economic losses for wine industry. In the present review, we summarize some recent efforts in the search of causative genes that account for yeast adaptation to low nitrogen environments, specially focused in wine fermentation conditions. We start presenting a brief perspective of yeast nitrogen utilization under wine fermentative conditions, highlighting yeast preference for some nitrogen sources above others. Then, we give an outlook of S. cerevisiae genetic diversity studies, paying special attention to efforts in genome sequencing for population structure determination and presenting QTL mapping as a powerful tool for phenotype-genotype correlations. Finally, we do a recapitulation of S. cerevisiae natural diversity related to low nitrogen adaptation, specially showing how different studies have left in evidence the central role of the TORC1 signalling pathway in nitrogen utilization and positioned wild S. cerevisiae strains as a reservoir of beneficial alleles with potential industrial applications (e.g. improvement of industrial yeasts for wine production). More studies focused in disentangling the genetic bases of S. cerevisiae adaptation in wine fermentation will be key to determine the domestication effects over low nitrogen adaptation, as well as to definitely proof that wild S. cerevisiae strains have potential genetic determinants for better adaptation to low nitrogen conditions.

Genetic aspects of type 1 diabetes

Type 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of pancreatic beta-cells in genetically predisposed individuals, eventually resulting in severe insulin deficiency. It is the most common form of diabetes in children and adolescents. Genetic susceptibility plays a crucial role in development of T1DM. The human leukocyte antigen complex plays a key role in the pathogenesis of T1DM. Furthermore, genome-wide association studies and linkage analysis have recently made a significant contribution to current knowledge relative to the impact of genetics on T1DM development and progression. This review focuses on current knowledge of genetics as a pathogenesis for T1DM. It also discusses mechanisms by which genes influence the risk of developing T1DM as well as the clinical and research applications of genetic risk scores in T1DM.

Genome-wide association study for birth, weaning and yearling weight in Colombian Brahman cattle

Abstract Genotypic and phenotypic data of 1,562 animals were analyzed to find genomic regions that potentially influence the birth weight (BW), weaning weight at seven months of age (WW) and yearling weight (YW) of Colombian Brahman cattle, with genotyping conducted using Illumina Bead chip array with 74,669 SNPs. A Single Step Genomic BLUP (ssGBLP), approach was used to estimate the proportion of variance explained by each marker. Multiple regions scattered across the genome were found to influence weights at different ages, also dependent on the trait component (direct or maternal). The most interesting regions were connected to previously identified QTLs and genes, such as ADAMTSL3, CAPN2, CAPN2, FABP6, ZEB2 influencing growth and weight traits. The identified regions will contribute to the development and refinement of genomic selection programs for Zebu Brahman cattle in Colombia.

The rs11191580 variant of the NT5C2 gene is associated with schizophrenia and symptom severity in a South Chinese Han population: evidence from GWAS

Objective: Recent genome-wide association studies have identified a significant relationship between the NT5C2 variant rs11191580 and schizophrenia (SCZ) in European populations. This study aimed to validate the association of rs11191580 polymorphism with SCZ risk in a South Chinese Han population. The relationship of this polymorphism with the severity of SCZ clinical symptoms was also explored. Methods: A case-control study was performed in 462 patients with SCZ and 598 healthy controls. Rs11191580 was genotyped by the Sequenom MassARRAY iPLEX platform. A total of 459 SCZ patients completed the Positive and Negative Syndrome Scale (PANSS) evaluation. Data were analyzed by PLINK software. Results: We confirmed an association of the rs11191580 polymorphism with SCZ risk in South Chinese Han under a dominant genetic model (ORadj = 0.769; 95%CIadj = 0.600-0.984; padj = 0.037). PANSS scores showed a significant association between variant rs11191580 and total score (padj = 0.032), lack of response scale score (padj = 0.022), and negative scale score (additive: padj = 0.004; dominant: padj = 0.016; recessive: padj = 0.021) after data were adjusted for age and sex. Conclusion: NT5C2 variant rs11191580 conferred susceptibility to SCZ and affected the clinical symptoms of SCZ in a South Chinese Han population.

Mendelian randomization approach, used for causal inferences / 中华流行病学杂志

Mendelian randomization (MR) approach is based on the Mendelian genetic law,which is called "Parental alleles that randomly assigned to the offspring".MR refers to the use of genetic variants to develop causal inferences from observational data,if the variant genotype isassociated with the phenotype and the variant genotype associated with the risk of disease of interest through the phenotype.Hence,the genotype can be used as Instrumental Variable (IV) to infer the causal relation between the phenotype and the risk of diseases.In recent years,MR approach is widely used in causal inference between the exposure factors and the risks of disease,along with the rapid development of statistical methods,big datasets of GWAS,epigenetics and the various "omics" techniques.This paper provides an overview of the MR strategies and addresses the related assumptions and implications,with reliability and limitations included.

Mendelian randomization approach, used for causal inferences / 中华流行病学杂志

Mendelian randomization (MR) approach is based on the Mendelian genetic law,which is called "Parental alleles that randomly assigned to the offspring".MR refers to the use of genetic variants to develop causal inferences from observational data,if the variant genotype isassociated with the phenotype and the variant genotype associated with the risk of disease of interest through the phenotype.Hence,the genotype can be used as Instrumental Variable (IV) to infer the causal relation between the phenotype and the risk of diseases.In recent years,MR approach is widely used in causal inference between the exposure factors and the risks of disease,along with the rapid development of statistical methods,big datasets of GWAS,epigenetics and the various "omics" techniques.This paper provides an overview of the MR strategies and addresses the related assumptions and implications,with reliability and limitations included.

Salt-sensitive genes and their relation to obesity / 한국영양학회지

PURPOSE: Although it is well known thatmortality and morbidity due to cardiovascular diseases are higher in salt-sensitive subjects than in salt-resistant subjects, their underlying mechanisms related to obesity remain unclear. Here, we focused on salt-sensitive gene variants unrelated to monogenic obesity that interacted with sodium intake in humans. METHODS: This review was written based on the modified 3(rd) step of Khans' systematic review. Instead of the literature, subject genes were based on candidate genes screened from our preliminary Genome-Wide Association Study (GWAS). Finally, literature related to five genes strongly associated with salt sensitivity were analyzed to elucidate the mechanism of obesity. RESULTS: Salt sensitivity is a measure of how blood pressure responds to salt intake, and people are either salt-sensitive or salt-resistant. Otherwise, dietary sodium restriction may not be beneficial for everyone since salt sensitivity may be associated with inherited susceptibility. According to our previous GWAS studies, 10 candidate genes and 11 single nucleotide polymorphisms (SNPs) associated with salt sensitivity were suggested, including angiotensin converting enzyme (ACE), α-adducin1 (ADD1), angiotensinogen (AGT), cytochrome P450 family 11-subfamily β-2 (CYP11β-2), epithelial sodium channel (ENaC), G-protein b3 subunit (GNB3), G protein-coupled receptor kinases type 4 (GRK4 A142V, GRK4 A486V), 11β-hydroxysteroid dehydrogenase type-2 (HSD 11β-2), neural precursor cell-expressed developmentally down regulated 4 like (NEDD4L), and solute carrier family 12(sodium/chloride transporters)-member 3 (SLC 12A3). We found that polymorphisms of salt-sensitive genes such as ACE, CYP11β-2, GRK4, SLC12A3, and GNB3 may be positively associated with human obesity. CONCLUSION: Despite gender, ethnic, and age differences in genetics studies, hypertensive obese children and adults who are carriers of specific salt-sensitive genes are recommended to reduce their sodium intake. We believe that our findings can contribute to the prevention of early-onset of chronic diseases in obese children by facilitating personalized diet-management of obesity from childhood to adulthood.

Genetics of osteoporosis: searching for candidate genes for bone fragility

ABSTRACT The pathogenesis of osteoporosis, a common disease with great morbidity and mortality, comprises environmental and genetic factors. As with other complex disorders, the genetic basis of osteoporosis has been difficult to identify. Nevertheless, several approaches have been undertaken in the past decades in order to identify candidate genes for bone fragility, including the study of rare monogenic syndromes with striking bone phenotypes (e.g. osteogenesis imperfecta and osteopetroses), the analysis of individuals or families with extreme osteoporotic phenotypes (e.g. idiopathic juvenile and pregnancy-related osteoporosis), and, chiefly, genome-wide association studies (GWAS) in large populations. Altogether, these efforts have greatly increased the understanding of molecular mechanisms behind bone remodelling, which has rapidly translated into the development of novel therapeutic strategies, exemplified by the tales of cathepsin K (CTSK) and sclerostin (SOST). Additional biological evidence of involvement in bone physiology still lacks for several candidate genes arisen from GWAS, opening an opportunity for the discovery of new mechanisms regulating bone strength, particularly with the advent of high-throughput genomic technologies. In this review, candidate genes for bone fragility will be presented in comprehensive tables and discussed with regard to how their association with osteoporosis emerged, highlighting key players such as LRP5, WNT1 and PLS3. Current limitations in our understanding of the genetic contribution to osteoporosis, such as yet unidentified genetic modifiers, may be overcome in the near future with better genotypic and phenotypic characterisation of large populations and the detailed study of candidate genes in informative individuals with marked phenotype.

Advances in genome-wide association studies of sporadic Alzheimer’s disease / 国际药学研究杂志

Alzheimer’s disease AD is a neurodegenerative disorder resulted from complicate interactions between genes and environment. There is no effective therapy so far. The genome-wide association study GWAS provides the opportunity to discover the risk genes of sporadic AD, which is informative for revealing the pathogenesis of AD and guiding new drug development. In this review, we summarize the current findings of genetic studies of AD, the risk genes and their biological relevance with AD, and new drug development strategy supported by genetic studies.

Advances in genome-wide association studies of sporadic Alzheimer′s disease / 国际药学研究杂志

Alzheimer′s disease(AD)is a neurodegenerative disorder resulted from complicate interactions between genes and environment. There is no effective therapy so far. The genome-wide association study(GWAS)provides the opportunity to discover the risk genes of sporadic AD,which is informative for revealing the pathogenesis of AD and guiding new drug development. In this re?view,we summarize the current findings of genetic studies of AD,the risk genes and their biological relevance with AD,and new drug development strategy supported by genetic studies.

Genome-wide association study for the interaction between BMR and BMI in obese Korean women including overweight

BACKGROUND/OBJECTIVES: This is the first study to identify common genetic factors associated with the basal metabolic rate (BMR) and body mass index (BMI) in obese Korean women including overweight. This will be a basic study for future research of obese gene-BMR interaction. SUBJECTS/METHODS: The experimental design was 2 by 2 with variables of BMR and BMI. A genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) was conducted in the overweight and obesity (BMI > 23 kg/m2) compared to the normality, and in women with low BMR (< 1426.3 kcal/day) compared to high BMR. A total of 140 SNPs reached formal genome-wide statistical significance in this study (P < 1 x 10(-4)). Surveys to estimate energy intake using 24-h recall method for three days and questionnaires for family history, a medical examination, and physical activities were conducted. RESULTS: We found that two NRG3 gene SNPs in the 10q23.1 chromosomal region were highly associated with BMR (rs10786764; P = 8.0 x 10(-7), rs1040675; 2.3 x 10(-6)) and BMI (rs10786764; P = 2.5 x 10(-5), rs10786764; 6.57 x 10(-5)). The other genes related to BMI (HSD52, TMA16, MARCH1, NRG1, NRXN3, and STK4) yielded P <10 x 10-4. Five new loci associated with BMR and BMI, including NRG3, OR8U8, BCL2L2-PABPN1, PABPN1, and SLC22A17 were identified in obese Korean women (P < 1 x 10(-4)). In the questionnaire investigation, significant differences were found in the number of starvation periods per week, family history of stomach cancer, coffee intake, and trial of weight control in each group. CONCLUSION: We discovered several common BMR- and BMI-related genes using GWAS. Although most of these newly established loci were not previously associated with obesity, they may provide new insights into body weight regulation. Our findings of five common genes associated with BMR and BMI in Koreans will serve as a reference for replication and validation of future studies on the metabolic rate.

Recent progress in the polygenic obesity among Asian population / 中华内分泌代谢杂志

Obesity has a harmful impact on health and is imposed by both environmental and genetic factors. Recently, over 60 obesity-related susceptible loci have been identified through genome-wide association study. However, it still remained unknown whether these loci were specific or generalized to the ethnic groups for genetic distinction. This review summarized the obesity-related susceptible loci in Asian populations, which were recently identified among Europeans or Asians.

Relationship between genetic variants in the Toll-like receptor pathway genes and susceptibility of gastric cancer and esophageal squamous cell carcinoma / 中华消化杂志

Objective To investigate the relationship between genetic variants in the Toll-like receptor (TLR) pathway genes and susceptibility of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC).Methods The data of whole genome association studies of the high-risk population of GC and ESCC in China were analyzed by adaptive rank-truncated product (ARTP) method in pathway and gene level.The associations between single nucleotide polymorphism (SNP) and susceptibility of GC and ESCC were analyzed with additive model of unconditional Logistic regressions.PLINK 1.07 and SPSS 19.0 software were performed for statistical analyses,and ARTP package in R3.0.2 was used for pathway and gene level analysis.Results In gene-level analyses,eight genes were found to be associated with susceptibility of GC (P ＜0.05) and six genes were associated with susceptibility of ESCC (P ＜ 0.05).In single SNP-level analyses,21 SNPs were statistically correlated with susceptibility of GC (P ＜ 0.01),and 11 SNPs were statistically correlated with susceptibility of ESCC (P ＜0.01).Conclusions Some genetic variants in TLR pathway are associated with risk of GC and ESCC.The potential molecular mechanisms need further investigation.

Susceptibility Genes for Multiple Sclerosis Identified in a Gene-Based Genome-Wide Association Study

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system. The aim of this study was to identify more genes associated with MS. METHODS: Based on the publicly available data of the single-nucleotide polymorphism-based genome-wide association study (GWAS) from the database of Genotypes and Phenotypes, we conducted a powerful gene-based GWAS in an initial sample with 931 family trios, and a replication study sample with 978 cases and 883 controls. For interesting genes, gene expression in MS-related cells between MS cases and controls was examined by using publicly available datasets. RESULTS: A total of 58 genes was identified, including 20 "novel" genes significantly associated with MS (p<1.40x10(-4)). In the replication study, 44 of the 58 identified genes had been genotyped and 35 replicated the association. In the gene-expression study, 21 of the 58 identified genes exhibited differential expressions in MS-related cells. Thus, 15 novel genes were supported by replicated association and/or differential expression. In particular, four of the novel genes, those encoding myelin oligodendrocyte glycoprotein (MOG), coiled-coil alpha-helical rod protein 1 (CCHCR1), human leukocyte antigen complex group 22 (HCG22), and major histocompatibility complex, class II, DM alpha (HLA-DMA), were supported by the evidence of both. CONCLUSIONS: The results of this study emphasize the high power of gene-based GWAS in detecting the susceptibility genes of MS. The novel genes identified herein may provide new insights into the molecular genetic mechanisms underlying MS.

Genetic & epigenetic approach to human obesity.

Obesity is an important clinical and public health challenge, epitomized by excess adipose tissue accumulation resulting from an imbalance in energy intake and energy expenditure. It is a forerunner for a variety of other diseases such as type-2-diabetes (T2D), cardiovascular diseases, some types of cancer, stroke, hyperlipidaemia and can be fatal leading to premature death. Obesity is highly heritable and arises from the interplay of multiple genes and environmental factors. Recent advancements in Genome-wide association studies (GWAS) have shown important steps towards identifying genetic risks and identification of genetic markers for lifestyle diseases, especially for a metabolic disorder like obesity. According to the 12th update of Human Obesity Gene Map there are 253 quantity trait loci (QTL) for obesity related phenotypes from 61 genome wide scan studies. Contribution of genetic propensity of individual ethnic and racial variations in obesity is an active area of research. Further, understanding its complexity as to how these variations could influence ones susceptibility to become or remain obese will lead us to a greater understanding of how obesity occurs and hopefully, how to prevent and treat this condition. In this review, various strategies adapted for such an analysis based on the recent advances in genome wide and functional variations in human obesity are discussed.

GWAS for sarcopenia related phenotype-univariate analysis and bivariate analy-sis / 中国免疫学杂志

Objective:To identify potentially pleiotropic genes for lean body mass ( LBM ) and age at menarche ( AAM).Methods:The discovery sample consisted of 1 692 unrelated female subjects of European ancestry.The replication sample consisted of 801 unrelated female subjects of Han Chinese ancestry.A total of 909,622 single nucleotide polymorphisms (SNPs) were genotyped in both samples with the Affymetrix genome-wide genotyping array SNP 6.0.Bivariate genome-wide association analyses were then performed to the appendicular LBM and AAM.Results: Two SNP rs1860547 and rs11030746 identified by the bivariate GWAS were significant at the genome-wide significance (GWS) level;their P-values were <0.05 after replications.In the upstream of rs1860547, two genes KCNA1 and KCNA5 were found to be important for both LBM and AAM.In the downstream of rs11030746, one gene KCNA4 was found.Univariate GWAS also identified both SNPs to be significant at the GWS level; their P-values were <0.05 after replications.In the upstream of rs1860547 , two genes KCNA1 and KCNA5 are found to be important for LBM.In the downstream of rs11030746 , one gene KCNA4 was found.Conclusion:KCNA1, KCNA4 and KCNA5 are likely to be pleiotropic genes closely related to both LBM and AAM in European females.

Replication of Interactions between Genome-Wide Genetic Variants and Body Mass Index in Fasting Glucose and Insulin Levels

The genetic regulation of glucose and insulin levels might be modified by adiposity. With regard to the genetic factors that are altered by adiposity, a large meta-analysis on the interactions between genetic variants and body mass index with regard to fasting glucose and insulin levels was reported by the Meta-Analyses of Glucose- and Insulin-related trait Consortium (MAGIC), based on European ancestry. Because no replication study has been performed in other ethnic groups, we first examined the link between reported single-nucleotide polymorphisms (SNPs) and fasting glucose and insulin levels in a large Korean cohort (Korean Genome and Epidemiology Study cohort [KoGES], n = 5,814). The MAGIC study reported 7 novel SNPs for fasting glucose levels and 6 novel SNPs for fasting insulin levels. In this study, we attempted to replicate the association of 5 SNPs with fasting glucose levels and 5 SNPs with fasting insulin levels. One SNP (rs2293941) in PDX1 was identified as a significant obesity-modifiable factor in Koreans. Our results indicate that the novel loci that were identified by MAGIC are poorly replicated in other ethnic groups, although we do not know why.