Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry

Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects ≈1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study meta-analysis was 2.4 × 10⁻⁶. We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P ≈ 10⁻⁷: 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 × 10⁻⁷) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.     

Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genome-wide significant result (P = 1.84 × 10⁻⁸) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.     

The association of genetically determined serum glycine with cardiovascular risk in East Asians

Background and aimsGlycine is involved in a wide range of metabolic pathways and increased circulating glycine is associated with reduced risk of cardio-metabolic diseases in Europeans but the genetic association between circulating glycine and cardiovascular risk is largely unknown in East Asians.Methods and resultsWe conducted a genome-wide association study (GWAS) in Singaporean Chinese participants and investigated if genetically determined serum glycine were associated with incident coronary artery disease (CAD) (711 cases and 1,246 controls), cardiovascular death (1,886 cases and 21,707 controls) and angiographic CAD severity (as determined by the Modified Gensini score, N = 1,138).ConclusionOur study, a first in East Asians, suggest a protective role of glycine against CAD.     

Chromogranin B P413L variant as risk factor and modifier of disease onset for amyotrophic lateral sclerosis

Recently, chromogranins were reported to interact specifically with mutant forms of superoxide dismutase that are linked to amyotrophic lateral sclerosis (ALS). This interaction led us to analyze the frequencies of sequence variants of the CHGB gene in ALS patients and matched controls from three different countries. Of particular interest was the finding of the P413L CHGB variant present in 10% of ALS patients (n = 705) as compared to 4.5% in controls (n = 751), conferring a 2.2-fold greater relative risk to develop the disease (P < 0.0001). This effect was mainly contributed by the samples of French origin that yielded a frequency of the P413L variation at 17% in ALS (n = 289) and 5% in controls (n = 448), conferring a 3.3-fold greater risk to develop ALS. Furthermore, the P413L CHGB variant is associated with an earlier age of onset by almost a decade in both sporadic ALS and familial ALS cases. Genetic variation influencing age of onset in ALS had not previously been reported. Expression of fusion CHGB-EGFP constructs in SHSY-5Y cells revealed that the P413L variation can cause defective sorting of CHGB into secretory granules. The finding that CHGB may act as a susceptibility gene and modifier of onset in ALS is consistent with the emerging view that dysfunction of the secretory pathway may contribute to increased vulnerability of motor neurons.     

药物基因组学在高血压药物治疗中的临床应用前景

高血压病及其相关的心血管疾病已成为导致死亡的首要原因之一;但全球药物降压达标率仍较低,其原因之一与个体间药物疗效差异较大相关,而药物的个体反应差异又很大程度与遗传背景有关.过去的10多年来,探讨高血压药物基因组学研究,以及寻找降压疗效相关基因方面进行了大量研究并取得成果;特别是部分β受体阻滞剂、钙离子拮抗剂,血管紧张素...     

Risk of chronic pancreatitis in carriers of the c.180C>T (p.Gly60=) CTRC variant: case-control studies and meta-analysis

Chymotrypsin C (CTRC) is a digestive serine protease produced by the pancreas that regulates intrapancreatic trypsin activity and provides a defensive mechanism against chronic pancreatitis (CP). CTRC exerts its protective effect by promoting degradation of trypsinogen, the precursor to trypsin. Loss-of-function missense and microdeletion variants of CTRC are found in around 4% of CP cases and increase disease risk by approximately 3-7-fold. In addition, a commonly occurring synonymous CTRC variant c.180C>T (p.Gly60=) was reported to increase CP risk in various cohorts but a global analysis of its impact has been lacking. Here, we analyzed the frequency and effect size of variant c.180C>T in Hungarian and pan-European cohorts, and performed meta-analysis of the new and published genetic association data. When allele frequency was considered, meta-analysis revealed an overall frequency of 14.2% in patients and 8.7% in controls (allelic odds ratio (OR) 2.18, 95% confidence interval (CI) 1.72–2.75). When genotypes were examined, c.180TT homozygosity was observed in 3.9% of CP patients and in 1.2% of controls, and c.180CT heterozygosity was present in 22.9% of CP patients and in 15.5% of controls. Relative to the c.180CC genotype, the genotypic OR values were 5.29 (95% CI 2.63–10.64), and 1.94 (95% CI 1.57–2.38), respectively, indicating stronger CP risk in homozygous carriers. Finally, we obtained preliminary evidence that the variant is associated with reduced CTRC mRNA levels in the pancreas. Taken together, the results indicate that CTRC variant c.180C>T is a clinically relevant risk factor, and should be considered when genetic etiology of CP is investigated.     

ICAM-1 molecular mechanism and genome wide SNP's association studies

Macrophages transformed foam cell formation occurs as a result of leukocyte accumulation mediated through intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and E-selectin, secreted by inflamed or damaged endothelium. The key molecule is the ICAM-1, member of the adhesion immunoglobulin super family that maps to chromosome 19 p13.2-p13.3 codes for 505 amino acids have five extracellular domains including circulatory leukocytes binding site (primarily monocytes) for recruiting it at the sites of inflammation and the tight adhesion with vascular endothelium for the above mentioned pathogenesis as an initial step. Hence the objective of the current paper is to review the Genome Wide Association (GWA) studies and summarizes its understanding of functional Single Nucleotide Polymorphism (SNP''s) of ICAM-1 clinical association to provide better guidance for the clinicians and researchers of the merits, demerits of the current results and direct them to do research on larger number of population for better prospective.     

Identification of a urate transporter,ABCG2, with a common functional polymorphism causing gout

Genome-wide association studies (GWAS) have successfully identified common single nucleotide polymorphisms (SNPs) associated with a wide variety of complex diseases, but do not address gene function or establish causality of disease-associated SNPs. We recently used GWAS to identify SNPs in a genomic region on chromosome 4 that associate with serum urate levels and gout, a consequence of elevated urate levels. Here we show using functional assays that human ATP-binding cassette, subfamily G, 2 (ABCG2), encoded by the ABCG2 gene contained in this region, is a hitherto unknown urate efflux transporter. We further show that native ABCG2 is located in the brush border membrane of kidney proximal tubule cells, where it mediates renal urate secretion. Introduction of the mutation Q141K encoded by the common SNP rs2231142 by site-directed mutagenesis resulted in 53% reduced urate transport rates compared to wild-type ABCG2 (P < 0.001). Data from a population-based study of 14,783 individuals support rs2231142 as the causal variant in the region and show highly significant associations with urate levels [whites: P = 10⁻³⁰, minor allele frequency (MAF) 0.11; blacks P = 10⁻⁴, MAF 0.03] and gout (adjusted odds ratio 1.68 per risk allele, both races). Our data indicate that at least 10% of all gout cases in whites are attributable to this causal variant. With approximately 3 million US individuals suffering from often insufficiently treated gout, ABCG2 represents an attractive drug target. Our study completes the chain of evidence from association to causation and supports the common disease-common variant hypothesis in the etiology of gout.     

Genetics of human obesity

This chapter presents the current state of knowledge in the field of the genetics of human obesity. The molecular approach has proved to be powerful in defining new syndromes associated with obesity. The pivotal role of leptin and melanocortin pathways has been recognized, but only in rare cases of obesity. In the more common form of obesity a multitude of polymorphisms located in genes and candidate regions throughout the genome regulate an individual's susceptibility to weight gain in a permissive environment. The effects are often uncertain and the results not always confirmed. Combining these single nucleotide polymorphisms and defining the associated risks for obesity will be a real challenge in the future. It is now necessary to integrate data of various origins (environment, genotype, expression) to clarify this field.     

Genetic-epidemiological evidence on genes associated with HDL cholesterol levels: A systematic in-depth review

High-density lipoprotein (HDL) particles exhibit multiple antiatherogenic effects. They are key players in the reverse cholesterol transport which shuttles cholesterol from peripheral cells (e.g. macrophages) to the liver or other tissues. This complex process is thought to represent the basis for the antiatherogenic properties of HDL particles. The amount of cholesterol transported in HDL particles is measured as HDL cholesterol (HDLC) and is inversely correlated with the risk for coronary artery disease: an increase of 1 mg/dL of HDLC levels is associated with a 2% and 3% decrease of the risk for coronary artery disease in men and women, respectively. Genetically determined conditions with high HDLC levels (e.g. familial hyperalphalipoproteinemia) often coexist with longevity, and higher HDLC levels were found among healthy elderly individuals.     

肥胖症全基因组关联分析研究进展

肥胖症的产生是由遗传和各种环境因素相互作用的结果。肥胖易感基因可以为肥胖症机制的研究提供重要的视角。全基因组关联分析（GWAS）的出现为研究肥胖易感基因提供了重要的途径。GWAS近来已经发现与肥胖强烈相关的新的遗传学因素,如脂肪含量和肥胖相关基因（FrO）,胰岛素诱导基因2（INSIG2）,血小板型磷酸果糖激酶（PFKP）等。目前,通过GWAS发现的一些肥胖易感基因还存在着争议,有待更多具有统计效能的重复性试验来证实。     

亚裔人群肥胖的多基因遗传研究进展

肥胖严重威胁人类健康,与遗传和环境关系密切。近年来,应用全基因组关联研究方法发现60余个肥胖有关性状的遗传位点,其在不同人群存在遗传异质性。本文就以亚裔人群为对象首次发现的肥胖有关性状的遗传位点和在亚裔人群中验证欧裔人群所定位的遗传位点两方面对肥胖多基因遗传研究最新进展进行综述。     

肾脏全基因组关联研究及发展方向

遗传因素在许多常见的肾脏疾病(如多囊肾病、Alport综合征、Fabry病、IgA肾病、糖尿病肾病、狼疮性肾炎等)中起着重要作用。以往数十年里,研究者为寻找这些常见肾脏疾病的基因变异,进行了大量的探索,通过连锁分析和定位克隆等技术研究明确了Alport综合征、Fabry病等单基因病的致病机制。但是,对临床上更为常见的复杂性疾病(IgA肾病、糖尿病肾病等)的基因研究进展却非常缓慢。近五年发展的全基因组关联研究(genome-wide association study,GWAS)为寻找这些疾病的易感基因提供了有力工具。     

Improving GWAS discovery and genomic prediction accuracy in biobank data

Genetically informed, deep-phenotyped biobanks are an important research resource and it is imperative that the most powerful, versatile, and efficient analysis approaches are used. Here, we apply our recently developed Bayesian grouped mixture of regressions model (GMRM) in the UK and Estonian Biobanks and obtain the highest genomic prediction accuracy reported to date across 21 heritable traits. When compared to other approaches, GMRM accuracy was greater than annotation prediction models run in the LDAK or LDPred-funct software by 15% (SE 7%) and 14% (SE 2%), respectively, and was 18% (SE 3%) greater than a baseline BayesR model without single-nucleotide polymorphism (SNP) markers grouped into minor allele frequency–linkage disequilibrium (MAF-LD) annotation categories. For height, the prediction accuracy R² was 47% in a UK Biobank holdout sample, which was 76% of the estimated hSNP2. We then extend our GMRM prediction model to provide mixed-linear model association (MLMA) SNP marker estimates for genome-wide association (GWAS) discovery, which increased the independent loci detected to 16,162 in unrelated UK Biobank individuals, compared to 10,550 from BoltLMM and 10,095 from Regenie, a 62 and 65% increase, respectively. The average χ2 value of the leading markers increased by 15.24 (SE 0.41) for every 1% increase in prediction accuracy gained over a baseline BayesR model across the traits. Thus, we show that modeling genetic associations accounting for MAF and LD differences among SNP markers, and incorporating prior knowledge of genomic function, is important for both genomic prediction and discovery in large-scale individual-level studies.

As biobank datasets increase in size, it is important to understand the factors limiting the prediction of phenotype from genotype. Alongside others, we have recently shown that genomic prediction accuracy can be improved through the use of random-effects models that incorporate prior knowledge of genomic annotations and allow for differences in the variance explained by single-nucleotide polymorphism (SNP) markers, depending upon their linkage disequilibrium (LD) and their minor allele frequency (MAF) (1–8). These improvements in prediction accuracy should also translate into greater genome-wide association study (GWAS) discovery power. Mixed-linear models of association (MLMA) are commonly applied in GWASs in a two-step approach, where a random-effects model is first used to estimate leave-one-chromosome-out (LOCO) genetic values, and these are then used in a second marginal regression coefficient estimation step. Theory suggests that the test statistics obtained in the MLMA second step depend upon the accuracy of the LOCO genomic predictors produced from the first step. Current MLMA implementations use a blocked ridge regression model (9), a Restricted Maximum Likelihood (REML) genomic relationship model (10), or a Bayesian spike-and-slab model (11) within the first step.Here, we improve the computational implementation of our recently developed Bayesian grouped mixture of regressions model (GMRM), which estimates genetic marker effects jointly, but with independent marker inclusion probabilities and independent hSNP2 parameters across LD, MAF, and functional annotation groups (Materials and Methods). This allows us to apply the model to 21 traits in the UK Biobank to test for prediction accuracy improvements over existing approaches. We then extend the model to provide MLMA SNP marker association estimates to test whether improved prediction accuracy translates to improved GWAS discovery compared to existing MLMA approaches.     

Linkage and association of successful aging to the 6q25 region in large Amish kindreds

Successful aging (SA) is a multidimensional phenotype involving living to older age with high physical function, preserved cognition, and continued social engagement. Several domains underlying SA are heritable, and identifying health-promoting polymorphisms and their interactions with the environment could provide important information regarding the health of older adults. In the present study, we examined 263 cognitively intact Amish individuals age 80 and older (74 SA and 189 “normally aged”) all of whom are part of a single 13-generation pedigree. A genome-wide association study of 630,309 autosomal single nucleotide polymorphisms (SNPs) was performed and analyzed for linkage using multipoint analyses and for association using the modified quasi-likelihood score test. There was evidence for linkage on 6q25-27 near the fragile site FRA6E region with a dominant model maximum multipoint heterogeneity LOD score = 3.2. The 1-LOD-down support interval for this linkage contained one SNP for which there was regionally significant evidence of association (rs205990, p = 2.36 × 10⁻⁵). This marker survived interval-wide Bonferroni correction for multiple testing and was located between the genes QKI and PDE10A. Other areas of chromosome 6q25-q27 (including the FRA6E region) contained several SNPs associated with SA (minimum p = 2.89 × 10⁻⁶). These findings suggest potentially novel genes in the 6q25-q27 region linked and associated with SA in the Amish; however, these findings should be verified in an independent replication cohort.

Electronic supplementary material

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