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Concept: Genetic epidemiology


Advances in sequencing technology and genome-wide association studies are now revealing the complex interactions between hosts and pathogen through genomic variation signatures, which arise from evolutionary co-existence.

Concepts: Immune system, DNA, Genetics, Molecular biology, Genome-wide association study, Genetic epidemiology


While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 (OR = 0.529, 95% CI 0.415-0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419-0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339-0.637; p = 3.04E-07) are correlated (r(2) > 0.5) and map at 15q12 in the region of HERC2/OCA2, which determines eye-color in the human population. Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility.

Concepts: Regression analysis, Logistic regression, Gene, Genetics, Population, Melanin, Uveal melanoma, Genetic epidemiology


Genome-wide association studies (GWASs) have been heralded as a major advance in biomedical discovery, having identified ~2,000 robust associations with complex diseases since 2005. Despite this success, they have met considerable scepticism regarding their clinical applicability; this scepticism arises from such aspects as the modest effect sizes of associated variants and their unclear functional consequences. There are, however, promising examples of GWAS findings that will or that may soon be translated into clinical care. These examples include variants identified through GWASs that provide strongly predictive or prognostic information or that have important pharmacological implications; these examples may illustrate promising approaches to wider clinical application.

Concepts: Medicine, Odds ratio, Genome-wide association study, The Association, Clinical research, Effect size, Genetic epidemiology


Genome-wide association study (GWAS) has been successful in identifying genetic variants that are associated with complex human diseases. In GWAS, multi-locus association analyses through linkage disequilibrium (LD), named haplotype-based analyses, may have greater power than single-locus analyses for detecting disease susceptibility loci. However, the large number of SNPs genotyped in GWAS poses great computational challenges in the detection of haplotype associations. We present a fast method named HapBoost for finding haplotype associations, which can be applied to quickly screen the whole genome. The effectiveness of HapBoost is demonstrated by using both synthetic and real datasets. The experimental results show that the proposed approach can achieve comparably accurate results while it performs much faster than existing methods.

Concepts: Genetics, Disease, Infectious disease, Genome-wide association study, Genetic linkage, Genetic association, Genetic epidemiology, Linkage disequilibrium


Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10(-9)), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10(-10)), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10(-9)), TRANK1 (Pbest=2.1 × 10(-9)) and ODZ4 (Pbest=3.3 × 10(-9)). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for ‘within Japanese comparisons’, Pbest~10(-29), R(2)~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for ‘trans-European-Japanese comparison,’ Pbest~10(-13), R(2)~0.27%). This ‘trans population’ effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD ‘risk’ effect are shared between Japanese and European populations.Molecular Psychiatry advance online publication, 24 January 2017; doi:10.1038/mp.2016.259.

Concepts: Gene, Genetics, Biology, Genome-wide association study, Japan, Effect size, Meta-analysis, Genetic epidemiology


Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie ‘hidden’ below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these ‘sub-threshold’ signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits.

Concepts: DNA, Gene, Genetics, Gene expression, Evolution, Biology, Genome-wide association study, Genetic epidemiology


Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10(-9), odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10(-10), OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10(-8), OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10(-11), OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10(-10), OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10(-9), OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10(-10), OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10(-10), OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10(-9), OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10(-8), OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10(-10), OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10(-11), OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10(-9), OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Concepts: Genetics, Brain tumor, Genome-wide association study, Identification, Genetic epidemiology


Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10(-8)) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52-0.73; P-value = 9.62 × 10(-9)). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55-0.76, P-value = 3.25 × 10(-8)). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.

Concepts: Genetics, Epidemiology, Infectious disease, Infection, Odds ratio, Genome-wide association study, Effect size, Genetic epidemiology


Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Concepts: DNA, Gene, Genetics, Biology, Genome-wide association study, Genetic linkage, Genetic association, Genetic epidemiology


Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL1RL1, were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.

Concepts: Gene, Genetics, Genotype, Evolution, Phenotype, Genome-wide association study, Francis Crick, Genetic epidemiology