Search

Aim The objective of the present meta-analysis was to investigate whether or not cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) polymorphisms are associated with ankylosing spondylitis (AS) susceptibility. Methods A systematic search was conducted from the PubMed, ENBASE, and Springer link database up to April 2014. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of association between CTLA-4 (+49 A/G) and AS risk. A subgroup analysis based on geographic region and a sensitivity analysis were also conducted. Results Five studies were eligible for meta-analysis, including 918 cases and 845 controls. The results showed that no significant association was found between AS and CTLA-4 (+49 A/G) for the additive model (G vs. A), dominant model (GG + AG vs. AA), co-dominant model (GG vs. AA, AG vs. AA) and recessive model (GG vs. AG + AA). The OR was 1.09 (95% CI, 0.87–1.38), 1.16 (95% CI, 0.89–1.51), 1.05 (95% CI, 0.75–1.46), 1.15 (95% CI, 0.86–1.52) and 0.99 (95% CI, 0.79–1.23), respectively. Although subgroup analysis demonstrated no association between CTLA-4 (+49 A/G) polymorphisms and susceptibility to AS in Europe and Taiwan, an association was found in Iran through both the co-dominant and dominant models. Exclusion of any individual study did not alter the significance of the final outcome, excepting the result by omitting the study by Huang et al. Conclusions The present results suggest that the CTLA-4 may not be a major susceptibility locus in humans with AS. The relationship between them may be affected by different geographic populations.

Background and Aims: There is a significant association between hepatitis C virus (HCV) infection and the risk of type 2 diabetes (T2D). However, the implications of genetic susceptibility loci for T2D in populations with HCV infection are unclear. We therefore conducted a study to detect susceptibility loci for T2D in Chinese infected with HCV. Methods: A total of 100 representative single-nucleotide polymorphisms (SNPs) in susceptibility loci for T2D that were previously reported in GWAS were genotyped in 762 Han Chinese with HCV infection by using illumina infinium iSelect HD Custom Genotyping BeadChips.

The data presented here are related to the research article, entitled Genetic analysis of atherosclerosis identifies a major susceptibility locus in the major histocompatibility complex of mice, published in Atherosclerosis 2016;254:124 (A.T. Grainger, M.B. Jones, J. Li, M.H. Chen, A. Manichaikul, W. Shi, 2016) [1]. The supporting materials include original genotypic and phenotypic data obtained from 206 female F2 mice derived from an intercross between BALB and SMJ inbred mice. The F2 mice were fed 12 weeks of Western diet, starting at 6 weeks of age. Atherosclerotic lesion size in the aortic root of each mouse is the sum of the top 8 lesion areas. The data is provided in the format required for determining QTLs using two independent programs, J/QTL and PLINK.

In a powerful display of international collaboration, a new genome-wide association study has mapped susceptibility loci for migraine on the basis of genetic data from 375,000 individuals. The study implicates several new loci in migraine — many of them suggestive of vascular pathophysiology — but the functional relevance of many now-detected risk alleles remains elusive.

We conducted a meta-analysis of genome-wide association studies (GWAS) with ∼16 million genotyped/imputed genetic variants in 62,892 type 2 diabetes (T2D) cases and 596,424 controls of European ancestry. We identified 139 common and 4 rare (minor allele frequency < 0.01) variants associated with T2D, 42 of which (39 common and 3 rare variants) were independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2,765) and other T2D-relevant tissues (n = up to 385) with the GWAS results identified 33 putative functional genes for T2D, three of which were targeted by approved drugs. A further integration of DNA methylation (n = 1,980) and epigenomic annotations data highlighted three putative T2D genes (CAMK1D, TP53INP1 and ATP5G1) with plausible regulatory mechanisms whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. We further found evidence that the T2D-associated loci have been under purifying selection.

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Here, we first introduce a multi-task learning method to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average of 39% improvement in imputation accuracy and generated effective imputation models for an average of 120% more genes. We describe a summary-statistic-based testing framework that combines multiple single-tissue associations into a powerful metric to quantify the overall gene-trait association. We applied our method, called UTMOST (unified test for molecular signatures), to multiple genome-wide-association results and demonstrate its advantages over single-tissue strategies.

Nature Communications 6: Article number: 6793 (2015); Published: 9 April 2015; Updated: 13 March 2018 In the originally published version of this Article, there were errors in the Methods section and in Supplementary Figure 2. In the Methods section entitled ‘Quality control’, and in Supplementary Figure 2, references to ‘MAF>0.

Two new neuroblastoma susceptibility loci at 3q25 (RSRC1 rs6441201 G > A) and 4p16 (CPZ rs3796725 T > C and rs3796727 A > G) were identified by a genome-wide association study (GWAS) involving Italians, African Americans and European Americans. In this case-control study with 393 neuroblastoma cases and 812 controls, we investigated the association between these three polymorphisms and neuroblastoma susceptibility in Chinese population. We found that participants harboring the RSRC1 rs6441201A allele were associated with an increased risk of neuroblastoma (AA vs. GG: adjusted OR = 1.55, 95% CI = 1.03–2.34, P = 0.036). No significant association between the CPZ polymorphisms (rs3796725 T > C and rs3796727A > G) and neuroblastoma susceptibility was observed. In conclusion, our results confirm that the RSRC1 rs6441201A allele is associated with neuroblastoma susceptibility in Chinese population.

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches., This work has been sponsored by the grant SEV-2011-00067 of Severo Ochoa Program, awarded by the Spanish Government. This work was supported by an EFSD/Lilly research fellowship. Josep M. Mercader was supported by Sara Borrell Fellowship from the Instituto Carlos III and Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR). Sílvia Bonàs was FI-DGR Fellowship from FI-DGR 2013 from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya). This study makes use of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. This study also makes use of data generated by the UK10K Consortium, derived from samples from UK10K COHORT IMPUTATION (EGAS00001000713). A full list of the investigators who contributed to the generation of the data is available in www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust under award WT091310. We acknowledge PRACE for awarding us to access MareNostrum supercomputer, based in Spain at Barcelona. The technical support group, particularly Pablo Ródenas and Jorge Rodríguez, from the Barcelona Supercomputing Center is gratefully acknowledged. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 667191. Mercè Planas-Fèlix is funded by the Obra Social Fundación la Caixa fellowship under the Severo Ochoa 2013 program. Work from Irene Miguel-Escalada, Ignasi Moran, Goutham Atla, and Jorge Ferrer was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, the Wellcome Trust (WT101033), Ministerio de Economía y Competitividad (BFU2014-54284-R) and Horizon 2020 (667191). Irene Miguel-Escalada has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska–Curie grant agreement No 658145. We acknowledge Prof. Giulio Cossu (Institute of Inflammation and Repair, University of Manchester) for providing the muscle myoblast cell line. We also acknowledge the InterAct and SIGMA Type 2 Diabetes Consortia for access to the data to replicate the rs146662075 variant. A full list of the investigators of the SIGMA Type 2 Diabetes and the InterAct consortia is provided in Supplementary Notes 3 and 4. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). This research has been conducted using the UK Biobank Resource (application number 16803). We also acknowledge Bianca C. Porneala, MS for his technical assistance in the collection and curation of the genotype and phenotype data from Partners Biobank. We also thank Marcin von Grotthuss for their support for uploading the summary statistics data to the Type 2 Diabetes Genetic Portal (AMP-T2D portal). Finally, we thank all the Computational Genomics group at the BSC for their helpful discussions and valuable comments on the manuscript.

To identify susceptibility loci for smoking dependence, more than 20 genome-wide linkage studies have been conducted in different populations using a variety of nicotine dependence (ND) assessment approaches, including smoking quantity (SQ), Heaviness of Smoking Index (HSI), Fagerstrom Test for Nicotine Dependence (FTND), ever smoking, habitual smoking, or maximum number of cigarettes smoked in a 24 h period (CPD). This chapter provides a critical summary of the susceptibility loci identified for ND and related measures. Although a great number of identified genomic regions did not reach the level of “suggestive” or “significant” linkage or failed to be replicated in independent studies, 14 regions, located on chromosomes 3–7, 9–11, 17, 20, and 22, have been found to be “suggestive” or “significant” linkages in at least two independent samples. Among them, the regions on chromosomes 9 (9q21.33-q33), 10, 11, and 17 have received the strongest support and deserve more attention in future genetic studies on ND.

Ischemic stroke, which is caused by blockage of vessels supplying blood to the brain, represents approximately 87% of all strokes in the United States. While a significant heritable component to ischemic stroke has been established, it is also clear that stroke is not a single “disease” but rather represents a heterogeneous collection of conditions with different pathogeneses. Genetic causes have been identified for a handful of monogenic syndromes that include stroke, but even collectively these conditions are very rare. To date, at least 10 robustly replicated susceptibility loci for nonmonogenic ischemic stroke have been identified, most of which are associated with specific stroke subtypes (especially large artery or cardioembolic stroke). The challenge will be to make sense of the known and to be discovered stroke susceptibility genes and to translate this knowledge into clinical benefit.

Hashimoto thyroiditis (HT) and Graves' disease (GD) share some immunological features. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these two related diseases.The aim of this study was to identify a non-HLA susceptibility locus that is specific to either HT or GD.We performed a two-stage genome-wide comparison between HT and GD in Japan. During the discovery stage, we performed a logistic regression analysis adjusting for sex using 727 413 single nucleotide polymorphisms (SNPs) for 265 HT and 261 GD patients. During the replication stage, 35 SNPs were analyzed for 181 HT and 286 GD cases. A combined meta-analysis was performed using the results from these two stages. An SNP showing a genome-wide significant level was further analyzed using 1363 healthy controls to determine the specificity of susceptibility.A genome-wide direct comparison between HT and GD revealed an SNP at the VAV3 locus with genome-wide significant association signals (rs7537605: P(combined) = 3.90 × 10(-8); odds ratio(combined) = 1.77; 95% confidence interval = 1.44-2.17). An association analysis using healthy controls showed that rs7537605 is significantly associated with HT (P = 1.24 × 10(-5); odds ratio = 1.60; 95% confidence interval = 1.30-1.97) but not with GD (P = .50), suggesting that the variant specifically affects susceptibility to HT.A genome-wide direct comparison between HT and GD revealed an HT-specific variant within VAV3 in the Japanese. Considering physiological roles of VAV3, such as a guanine nucleotide exchange factor, our finding provides new insight into the molecular mechanism of HT.

Cervical cancer has a heritable genetic component. A large number of genetic associations with cervical cancer have been reported in hypothesis-driven candidate gene studies, but many of these results are either inconsistent or have failed to be independently replicated. Genome-wide association studies (GWAS) have identified additional susceptibility loci previously not implicated in cervical cancer development, highlighting the power of genome-wide unbiased association analyses. Post-GWAS analyses including pathway-based analysis and functional characterization of associated variants have provided new insights into the pathogenesis of cervical cancer. In this review we summarize findings from candidate gene association studies, GWAS, and post-GWAS analyses of cervical cancer. We also discuss gaps in our understanding, possible clinical implications of the findings, and lessons for studies of other complex diseases.

We report a 42-year-old female with a 20-year history of systemic lupus erythematosus who subsequently developed psoriasis vulgaris. She has been on chronic, erratic prednisone and hydroxychloroquine intake prior to appearance of psoriatic lesions. Hydroxychloroquine and glucocorticoids are possible triggers of this phenomenon. Both diseases have a shared susceptibility loci and a shared Th17 pathophysiologic pathway. Treatment with methotrexate and selected biologics can target both disease mechanisms.

The present study evaluated 23 newly identified susceptibility loci for prostate cancer (PCa) in a Chinese population and assessed whether any validated loci were associated with the genetic risk score (GRS) of PCa in a Chinese population. A total of 1,417 patients with PCa and 1,008 controls were recruited in the present study. The association of each single nucleotide polymorphism (SNP) with PCa risk and PCa aggressiveness was analyzed. The predictive ability of two GRSs based on 30 SNPs (GRS30) and the 9 most significant SNPs (GRS9) in the Chinese population were also compared. Among the 19 SNPs evaluated, 1 SNP (rs7153648 at 14q23) was associated with PCa risk [odds ratio (OR)=1.206, P

PURPOSE OF REVIEW: More than 80 susceptibility loci are now reported to show robust genetic association with systemic lupus erythematosus (SLE). The differential functional effects of the risk alleles for the majority of these loci remain to be defined. Here, we review current SLE association findings and the recent progress in the annotation of noncoding regions of the human genome as well as the new technologies and statistical methods that can be applied to further the understanding of SLE genetics.RECENT FINDINGS: Genome-wide association studies (GWAS) have markedly expanded the catalogue of genetic signals contributing to SLE development; we can now explain more than 50% of the disease's heritability. Expression quantitative trait loci mapping with colocalization analysis of GWAS results help to identify the underlying causal genes. The Encyclopedia of DNA elements, Roadmap Epigenome, and the Blueprint Epigenome projects have jointly annotated more than 80% of the noncoding genome, providing a wealth of information (from healthy individuals) to define the functional elements within the risk loci. Technologies, such as next-generation sequencing, chromatin structure determination, and genome editing, will help elucidate the actual mechanisms that underpin SLE risk alleles.SUMMARY: Gene expression and epigenetic databases provide a valuable resource to interpret genetic association in SLE. Expansion of such resources to include disease status and multiple ancestries will further aid the exploration of the biology underlying the genetics.

It is well-known that breast tumors exhibit different expression patterns that can be used to assign intrinsic subtypes – the PAM50 assay, for example, categorizes tumors into: Luminal A, Luminal B, HER2-enriched and Basal-like – yet tumors are often more complex than categorization can describe. We used 911 sporadic breast tumors to reparameterize expression from the PAM50 genes to five orthogonal tumor dimensions using principal components (PC). Three dimensions captured intrinsic subtype, two dimensions were novel, and all replicated in 945 TCGA tumors. By definition dimensions are independent, an important attribute for inclusion in downstream studies exploring effects of tumor diversity. One application where tumor subtyping has failed to provide impact is susceptibility genetics. Germline genetic heterogeneity reduces power for gene-finding. The identification of heritable tumor characteristics has potential to increase homogeneity. We compared 238 breast tumors from high-risk pedigrees not attributable to BRCA1 or BRCA2 to 911 sporadic breast tumors. Two PC dimensions were significantly enriched in the pedigrees (intrinsic subtypes were not). We performed proof-of-concept gene-mapping in one enriched pedigree and identified a 0.5 Mb genomewide significant region at 12q15 that segregated to the 8 breast cancer cases with the most extreme PC tumors through 32 meioses (p=2.6×10−8). In conclusion, our study: suggests a new approach to describe tumor diversity; supports the hypothesis that tumor characteristics are heritable providing new avenues for germline studies; and proposes a new breast cancer locus. Reparameterization of expression patterns may similarly inform other studies attempting to model the effects of tumor heterogeneity.

Multi-ancestry genome-wide association study (GWAS) has recently identified 11 new susceptibility loci for Atopic dermatitis (AD). The replication of these new susceptibility loci in different populations should not be ignored.To examine whether these 11 new identified susceptibility loci are also associated with AD in the Chinese Han population.These 11 variants were imputed using our genome-wide array dataset. The selected SNPs with suggestive signals were genotyped in a large-scale replication study with a total of 4619 cases and 10,789 controls using the Sequenom Massarray system. Association analyses were performed using PLINK 1.07 software. Results were combined across our previous AD-GWAS stage and the replication stage by meta-analysis. Bioinformatic analysis was done to predict the possible causal gene.Of the 11 SNPs investigated, four SNPs showed suggestive association (P0.05) in our previously published GWAS datasets. Association evidence for an intergenic variant rs112111458 at 2p13.3 with AD was replicated in Chinese Han population (P=7.37×10Our study confirmed a previously reported susceptibility loci in the Chinese Han population, which implicates CD207 might be a new susceptibility gene for AD and highlights the crucial role of immune responses in AD.

Pattern hair loss is the most common form of hair loss in both women and men. Male pattern hair loss, also termed male androgenetic alopecia (M-AGA), is an androgen-dependent trait that is predominantly genetically determined. Androgen-mediated mechanisms are probably involved in female pattern hair loss (FPHL) in some women but the evidence is less strong than in M-AGA; other non-androgenic pathways, including environmental influences, may contribute to the aetiology. Genome-wide association studies have identified several genetic loci for M-AGA and have provided better insight into the underlying biology. However, the role of heritable factors in Female Pattern Hair Loss (FPHL) is largely unknown. Recently published studies have been restricted to candidate gene approaches and could not clearly identify any susceptibility locus/gene for FPHL but suggest that the aetiology differs substantially from that of M-AGA. Hypotheses about possible pathomechanisms of FPHL as well as the results of the genetic studies performed to date are summarized.

Genomic array detects more pathogenic chromosome aberrations than conventional karyotyping (CK), including genetic variants associated with a susceptibility for neurodevelopmental disorders; susceptibility loci (SL). Consensus regarding the scope of invasive prenatal diagnosis (PND) pregnant couples should be offered is lacking. This study examined pregnant couples' preferences, doubts and satisfaction regarding the scope of invasive PND. Eighty-two couples choosing prenatal screening (PNS) and 59 couples choosing invasive PND were offered a choice between 5 (comparable to CK) and 0.5 Mb resolution array analysis outcomes, the latter with or without reporting SL. A pre-test self-report questionnaire and post-test telephone interview assessed their choices in-depth. Actual (PND) and hypothetical (PNS) choices differed significantly (p

We examined the role of Mag, an autoimmune susceptibility locus encoded by the telomeric region of MRL/MpJ mouse chromosome 1, in the pathogenesis of autoimmune exocrinopathy. At nine to 12 months of age, strain-specific differences were observed in the pancreas of the animals. B- and T-cell-containing periductal/perivascular cell infiltrations in the pancreases of MRL/MpJ and B6.MRLc1 congenic C57BL/6-background Mag-carrying strains were more severe than were those of C57BL/6. Pancreatic periductal/perivascular cell infiltration was observed frequently in A/J, AKR/N, B6.MRLc1, C57BL/6, and MRL/MpJ, moderately in DBA/1 and DBA/2, and rarely in BALB/c and C3H/He strains. Females tended to have greater pancreatic periductal/perivascular cell infiltration than males. C57BL/6 mice possessed defined borders between cell infiltrations and acini, but borders were indistinct in MRL/MpJ and B6.MRLc1 mice. We attributed this to the invasion of inflammatory cells between each acinus and the disruption of acinar cells around cell infiltrations in the latter strains. No strain-specific differences were observed in the appearance of fibrotic lesions and high endothelial venules in the cell infiltrates. The levels of serum anti-dsDNA antibodies and amylase, and mRNA expression of tumor necrosis factor-α and Fc gamma receptor III (encoded on Mag) in the pancreases, were elevated in MRL/MpJ- and B6.MRLc1-strain mice relative to C57BL/6. These results emphasized the crucial roles of Mag in the molecular and genetic pathogenesis of autoimmune-mediated pancreatitis.

Neuroblastoma (NB) is an embryonal tumor of the sympathetic nervous system which accounts for 8-10% of pediatric cancers. It is characterized by a broad spectrum of clinical behaviors from spontaneous regression to fatal outcome despite aggressive therapies. Considerable progress has been made recently in the germline and somatic genetic characterization of patients and tumors. Indeed, predisposition genes that account for a significant proportion of familial and syndromic cases have been identified and genome-wide association studies have retrieved a number of susceptibility loci. In addition, genome-wide sequencing, copy-number and expression studies have been conducted on tumors and have detected important gene modifications, profiles and signatures that have strong implications for the therapeutic stratification of patients. The identification of major players in NB oncogenesis, including MYCN, ALK, PHOX2B and LIN28B, has enabled the development of new animal models. Our review focuses on these recent advances, on the insights they provide on the mechanisms involved in NB development and their applications for the clinical management of patients.

Vitiligo is a common acquired depigmentation disorder of the skin manifested by the presence of white macules. The disease occurs at a frequency of approximately 1–4% of the world population. Currently, the most popular theory of vitiligo development is a multifactorial hypothesis according to which genetic conditions predispose vitiligo macules to occur as a result of specific environmental factors. According to the genetic hypothesis, vitiligo inheritance is multigenic. Genetic studies conducted so far concern patients with non-segmental vitiligo. There are three basic techniques of genetic studies: candidate gene association studies, genomewide linkage studies and genome-wide association studies (GWAS). The GWAS are the “gold standard” for detecting susceptibility genes. Up to now, approximately 36 convincing non-segmental vitiligo susceptibility loci have been identified. Approximately 90% of them encode immunoregulatory proteins, while approximately 10% encode melanocyte proteins. The existence of various associations between vitiligo and other autoimmune diseases may provide new knowledge on the causes of many disorders. Examples include the inverse relationship between vitiligo and melanoma and association of vitiligo with other autoimmune diseases. The main goal of all researches is to find new, optimal therapeutic strategies for vitiligo and other autoimmune diseases.

Studies in European populations have contributed to a better understanding of the genetics of complex diseases, for example, in coeliac disease (CeD), studies of over 23 000 European samples have reported association to the HLA locus and another 39 loci. However, these associations have not been evaluated in detail in other ethnicities. We sought to better understand how disease-associated loci that have been mapped in Europeans translate to a disease risk for a population with a different ethnic background. We therefore performed a validation of European risk loci for CeD in 497 cases and 736 controls of north Indian origin. Using a dense-genotyping platform (Immunochip), we confirmed the strong association to the HLA region (rs2854275, P = 8.2 x 10(-49)). Three loci showed suggestive association (rs4948256, P = 9.3 x 10(-7), rs4758538, P = 8.6 x 10(-5) and rs17080877, P = 2.7 x 10(-5)). We directly replicated five previously reported European variants (Po0.05; mapping to loci harbouring FASLG/TNFSF18, SCHIP1/IL12A, PFKFB3/PRKCQ, ZMIZ1 and ICOSLG). Using a transferability test, we further confirmed association at PFKFB3/PRKCQ (rs2387397, P = 2.8 x 10(-4)) and PTPRK/THEMIS (rs55743914, P = 3.4 x 10(-4)). The north Indian population has a higher degree of consanguinity than Europeans and we therefore explored the role of recessively acting variants, which replicated the HLA locus (rs9271850, P = 3.7 x 10(-23)) and suggested a role of additional four loci. To our knowledge, this is the first replication study of CeD variants in a non-European population.

Dietary factors may affect risk of renal cell carcinoma (RCC). In an ongoing case-control study of RCC initiated in Houston, Texas, in 2002, we identified 3 empirically derived dietary patterns: “fruits and vegetables,” “American/Western,” and “Tex-Mex.” Among 659 RCC cases and 699 controls, we evaluated associations of these dietary patterns with RCC risk and whether the associations varied by obesity status, smoking status, physical activity level, history of hypertension, and genetic variants previously identified via genome-wide association studies. Among persons in the highest categories of adherence versus the lowest, the “fruits and vegetables” dietary pattern was associated with an approximately 50% lower RCC risk (Ptrend < 0.001), while “American/Western” dietary pattern scores were positively associated with a 2-fold higher risk (Ptrend < 0.001). We observed synergistic interaction between the American/Western pattern and hypertension status: The odds ratio (highest tertile vs. lowest) among persons with hypertension was 2.23 (95% confidence interval: 1.43, 3.45), as compared with 1.76 (95% confidence interval: 1.16, 2.70) among persons without hypertension (additive Pinteraction = 0.01). A variant (rs718314) in the inositol 1,4,5-trisphosphate receptor, type 2 gene (ITPR2) was found to interact with the American/Western dietary pattern in relation to RCC risk (additive Pinteraction = 0.03). ITPR2 has been shown to affect nutrient metabolism and central obesity. Dietary patterns, genetic variants, and host characteristics may individually and jointly influence susceptibility to RCC.

In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified three novel genetic loci associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene, P = 8.82 × 10−9), rs10474352 at 5q14.3 (near the ARRDC3 gene, P = 1.67 × 10−9), and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene, P = 4.25 × 10−8). These associations were replicated in European-ancestry populations including 16,003 cases and 41,335 controls (P = 0.030, 0.004, and 0.010, respectively). Data from the ENCODE project suggest that variants rs4951011 and rs10474352 may be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.

A genome-wide nonparametric linkage screen was performed to localize Bipolar Disorder (BP) susceptibility loci in a sample of 3757 individuals of Latino ancestry. The sample included 963 individuals with BP phenotype (704 relative pairs) from 686 families recruited from the US, Mexico, Costa Rica, and Guatemala. Non-parametric analyses were performed over a 5 cM grid with an average genetic coverage of 0.67 cM. Multipoint analyses were conducted across the genome using non-parametric Kong & Cox LOD scores along with Sall statistics for all relative pairs. Suggestive and significant genome-wide thresholds were calculated based on 1000 simulations. Single-marker association tests in the presence of linkage were performed assuming a multiplicative model with a population prevalence of 2%. We identified two genome-wide significant susceptibly loci for BP at 8q24 and 14q32, and a third suggestive locus at 2q13-q14. Within these three linkage regions, the top associated single marker (rs1847694, P = 2.40 × 10(-5)) is located 195 Kb upstream of DPP10 in Chromosome 2. DPP10 is prominently expressed in brain neuronal populations, where it has been shown to bind and regulate Kv4-mediated A-type potassium channels. Taken together, these results provide additional evidence that 8q24, 14q32, and 2q13-q14 are susceptibly loci for BP and these regions may be involved in the pathogenesis of BP in the Latino population.

ABSTRACT: Prostate cancer (PrCa) is the most commonly diagnosed cancer in the male UK population, with over 40,000 new cases per year. PrCa has a complex, polygenic predisposition, due to rare variants such as BRCA and common variants such as single nucleotide polymorphisms (SNPs). With the introduction of genome-wide association studies, 78 susceptibility loci (SNPs) associated with PrCa risk have been identified. Genetic profiling could risk-stratify a population, leading to the discovery of a higher proportion of clinically significant disease and a reduction in the morbidity related to age-based prostate-specific antigen screening. Based on the combined risk of the 78 SNPs identified so far, the top 1% of the risk distribution has a 4.7-times higher risk of developing PrCa compared with the average of the general population.

The Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study was a large 3-year observational controlled multicentre international study aimed at defining clinically relevant subtypes of chronic obstructive pulmonary disease (COPD) and identifying novel biomarkers and genetic factors. So far, the ECLIPSE study has produced more than 50 original publications and 75 communications to international meetings, many of which have significantly influenced our understanding of COPD. However, because there is not one paper reporting the biomarker results of the ECLIPSE study that may serve as a reference for practising clinicians, researchers and healthcare providers from academia, industry and government agencies interested in COPD, we decided to write a review summarising the main biomarker findings in ECLIPSE.

The pathogenesis of primary sclerosing cholangitis (PSC) involves heritable factors. This review summarizes the recent genetic studies and discusses the implications of identified risk loci.A total of 16 PSC susceptibility loci have been identified in genome-wide association studies and related study designs. At least 33 additional loci are involved in what is increasingly acknowledged to represent a general pool of genetic risk loci for immune-mediated diseases. One important group of genes is part of well characterized immune pathways (e.g. interleukin 2 signaling), whereas for other loci the relationship to PSC pathophysiology is less evident. Importantly, the loci collectively account for only 7.3% of overall PSC liability, thus pointing to a large contribution from environmental factors to PSC development. The individual PSC risk genes cannot be interpreted within a simple cause-effect model used for monogenic traits, but need to be explored for their individual biological correlates, preferably in a disease context. To some extent, as exemplified for the human leukocyte antigen and FUT2 associations, genetic findings may guide the discovery of interacting and co-occuring environmental susceptibility factors.Multiple PSC susceptibility loci are now available for exploration in experimental model systems and patient-centered research.

Genome-wide association studies (GWAS) using single nucleotide polymorphism (SNP) markers have identified more than 3800 susceptibility loci for more than 660 diseases or traits. However, the most significantly associated variants or causative variants in these loci and their biological functions have remained to be clarified. These causative variants can help to elucidate the pathogenesis and discover new biomarkers of complex diseases. One of the main goals in the post-GWAS era is to identify the causative variants and susceptibility genes, and clarify their functional aspects by fine mapping. For common variants, imputation or re-sequencing based strategies were implemented to increase the number of analyzed variants and help to identify the most significantly associated variants. In addition, functional element, expression quantitative trait locus (eQTL) and haplotype analyses were performed to identify functional common variants and susceptibility genes. For rare variants, fine mapping was carried out by re-sequencing, rare haplotype analysis, family-based analysis, burden test, etc.This review summarizes the strategies and problems for fine mapping.

Psoriasis is a complex immune-mediated disease of skin and joints with a prevalence of about 2%. Previous genetic association studies have identified more than 60 psoriasis susceptibility loci, 47 of which were identified in Caucasians. To further understand the genetic architecture of this disease, we conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts (seven GWAS and one Immunochip dataset), with a combined effective sample size of more than 39,000 individuals. Approximately half (n = 22) of the 47 European-origin loci were identified in cohorts containing a large proportion (≥50%) of samples genotyped using the Immunochip (Bowes et al., 2015; Stuart et al., 2015; Tsoi et al., 2012a, 2015), a platform that focuses on genetic variants from promising signals identified in previous association studies of autoimmune diseases (Stuart et al., 2015). However, restricting analysis to markers genotyped (∼110,000) (Tsoi et al., 2012b) or well-imputed (∼700,000) (Tsoi et al., 2015) on the Immunochip limits exploration of the full genome for susceptibility loci.

BACKGROUND & AIMS: Crohn’s disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progresses to complicated disease, which includes stricturing (B2) within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn’s disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. METHODS: We obtained blood samples from 164 pediatric patients (ages, 1–17 years) with Crohn’s disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms were used as controls (n=74). DNA methylation patterns were analyzed at approximately 850,000 sites, in samples collected at time of diagnosis and 1–3 years later. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to development of or result from Crohn’s disease. RESULTS: We identified 1189 CpGs that were differentially methylated between patients with Crohn’s disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn’s disease vs during the follow-up period revealed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn’s disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpGs that might contribute to the development of Crohn’s disease. Most CpG methylation changes associated with Crohn’s disease disappeared with treatment of inflammation, and might be a result of Crohn’s disease. CONCLUSIONS: Methylation patterns observed in blood samples from patients with Crohn’s disease accompany acute inflammation; with treatment, they change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn’s disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.

C. Tziotzios, Genomewide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02. Nature Communications . 2019(Mar 8); 10(1):1150.2019(Mar) ![][1] Frontal fibrosing alopecia (FFA) is an inflammatory scarring alopecia that was first