Evidence For Association Of Variants Research Articles

Candidate gene expression and coding sequence variants in Warmblood horses with myofibrillar myopathy.

Myofibrillar myopathy (MFM) of unknown aetiology has recently been identified in Warmblood (WB) horses. In humans, 16 genes have been implicated in various MFM-like disorders. To identify variants in 16 MFM candidate genes and compare allele frequencies of all variants between MFM WB and non-MFM WB and coding variants with moderate or severe predicted effects in MFM WB with publicly available data of other breeds. To compare differential gene expression and muscle fibre contractile force between MFM and non-MFM WB. Case-control. 8 MFM WB, 8 non-MFM WB, 33 other WB, 32 Thoroughbreds, 80 Quarter Horses and 77 horses of other breeds in public databases. Variants were called within transcripts of 16 candidate genes using gluteal muscle mRNA sequences aligned to EquCab3.0 and allele frequencies compared by Fisher's exact test among MFM WB, non-MFM WB and public sequences across breeds. Candidate gene differential expression was determined between MFM and non-MFM WB by fitting a negative binomial generalised log-linear model per gene (false discovery rate <0.05). The maximal isometric force/cross-sectional area generated by isolated membrane-permeabilised muscle fibres was determined. None of the 426 variants identified in 16 candidate genes were associated with MFM including 26 missense variants. Breed-specific differences existed in allele frequencies. Candidate gene differential expression and muscle fibre-specific force did not differ between MFM WB (143.1±34.7kPa) and non-MFM WB (140.2±43.7kPa) (P=.8). RNA-seq-only assays transcripts expressed in skeletal muscle. Other possible candidate genes were not evaluated. Evidence for association of variants with a disease is essential because coding sequence variants are common in the equine genome. Variants identified in MFM candidate genes, including two coding variants offered as commercial MFM equine genetic tests, did not associate with the WB MFM phenotype.

Sequence Variants in TBX6 Are Associated with Disorders of the Müllerian Ducts: An Update

Müllerian anomalies comprise the Mayer-Rokitansky-Küster-Hauser syndrome as well as fusion defects of the müllerian ducts. Recurrent micro-aberrations like deletions in 16p11.2 encompassing TBX6 were found to be causative in these patients. TBX6 encodes a transcription factor which plays a role in paraxial mesoderm differentiation/specification. In previous studies, we and other groups found possibly pathogenic variants in TBX6 in patients with müllerian anomalies. Since we suggested TBX6 as a strong candidate, we performed sequential analysis of the TBX6 gene in additional 125 patients with müllerian anomalies, and 2 possibly pathogenic missense variants and 1 nonsense substitution in TBX6 in 4/125 patients were found. The missense variant c.484G>A, which we have described in a previous study, was reidentified but with no higher frequency as in our controls. We detected 3 possibly pathogenic variants in TBX6 and could show that the variant c.484G>A is not causative for disorders of the müllerian ducts in the non-Finnish European population. In summary, we present increasing evidence for association of variants in TBX6 with malformations of the müllerian ducts.

Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study.

Background: Genetic research may inform underlying mechanisms for disparities in the burden of type 2 diabetes mellitus among American Indians. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS).Methods and Results: We examined the association of variants, previously associated with cardiometabolic traits (∼200,000 from Illumina Cardio MetaboChip), using mixed models of HOMA-B residuals corrected for HOMA-IR (cHOMA-B), log transformed HOMA-IR, and incident diabetes, adjusted for age, sex, population stratification, and familial relatedness. Center-specific estimates were combined using fixed effect meta-analyses. We used Bonferroni correction to account for multiple testing (P < 4.13 × 10−7). We also assessed the association between variants in candidate diabetes genes with these metabolic traits. We explored the top SNPs in an independent, replication sample from Southwestern Arizona. We identified significant associations with cHOMA-B for common variants at 26 loci of which 8 were novel (PRSS7, FCRL5, PEL1, LRP12, IGLL1, ARHGEF10, PARVA, FLJ16686). The most significant variant association with cHOMA-B was observed on chromosome 5 for an intergenic variant near PARP8 (rs2961831, P = 6.39 × 10−9). In the replication study, we found a signal at rs4607517 near GCK/YKT6 (P = 0.01). Variants near candidate diabetes genes (especially GCK and KCNQ1) were also nominally associated with HOMA-IR and cHOMA-B.Conclusion: We identified variants at novel loci and confirmed those at known candidate diabetes loci associations for cHOMA-B. This study also provided evidence for association of variants at KCNQ2, CTNAA2, and KCNQ1with cHOMA-B among American Indians. Further studies are needed to account for the high heritability of diabetes among the American Indian participants of the SHFS cohort.

Abstract 1289: Evaluation of vitamin D receptor regulated genes reveals EGFR polymorphism is associated with high-grade serous ovarian cancer in African American women

Abstract Few studies have evaluated genetic risk factors for ovarian cancer in African American women. In a previous study with small sample sizes, Vitamin D Receptor (VDR) variants were shown to increase risk of epithelial ovarian cancer (EOC) in that population. This study sought to replicate those findings and assess gene variants from the VDR regulatory pathway. We assessed SNPs (genotyped+imputed) from 5 gene regions which included VDR and genes regulated by VDR, including UGT1A, UGT2B, CYP3A4/5 and EGFR in 755 EOC cases and 1,235 controls among women of African ancestry from the Ovarian Cancer Association Consortium (OCAC). We also performed analyses restricted to 537 patients with HGSOC represented in the overall analysis of EOC. SNPs were genotyped using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set for genotyped and imputed SNPs evaluated at the 5 gene regions (918 SNPs in UGT1A, 6302 SNPs in UGT2B, 410 SNPs in CYP3A4/5, and 824 SNPs in EGFR). Logistic regression was performed using an additive 1 degree of freedom model for genetic inheritance with adjustment for two principal components of ancestry to estimate odds ratios (OR) and 95 % confidence intervals (CI). For each gene region, we applied a gene-specific Bonferroni-threshold for statistical significance defined as 0.05 / number of SNPs examined for that gene. Based on this significance threshold, a statistically significant association with HGSOC was identified in the EGFR region for the imputed SNP, rs114972508 (per allele OR = 2.32, 95% CI = 1.58, 3.40 p=1.6e-05, imputation R-squared=0.89). We further identified suggestive associations (P &amp;lt; 1.0e-06) with EOC for 10 imputed SNPs located within the UGT2B4 gene. We did not replicate previous associations in the 282 SNPs examined in the VDR gene for EOC overall or among HGSOC. In summary, we identified statistically significant association for variants from the EGFR region, and suggestive evidence of association for variants within the UGT2B region in genetic association analyses of ovarian cancer in women of African Ancestry. Data from in vitro experiments suggest that EGFR transcription and proliferative function is suppressed via VDR binding. Thus EGFR association with HGSOC may be a marker of VDR activity. UGT2B4 variants have not been previously explored in ovarian cancer but shown to be nominally associated with breast cancer in women of African ancestry. UGT2B4 enzymes, part of the phase II liver detoxification pathway, are important in the clearance of steroid hormones, bile acid and drug metabolism. Alterations in EGFR and UGT2B4 could perturb enzyme efficacy and proliferation in ovaries and impact susceptibility to ovarian cancer. Future studies will be needed to validate the associations of the imputed SNPs and to determine the impact of EGFR and UGT variants on cancer development. Citation Format: Delores J. Grant, Ani Manichaikul, Lauren C. Peres, Xin-Qun Wang, Ann G. Schwartz, Anna Wu, Edward Peters, Patricia Moorman, Michele L. Cote, Melissa Bondy, Linda E. Kelemen, Jill Barnholtz-Sloan, Temitope O. Keku, Cathrine Hoyo, Andrew Berchuck, Paul Pharoah, Joellen M. Schildkraut, African American Cancer Epidemiology Study (AACES) and the Ovarian Cancer Assoc Consortium (OCAC). Evaluation of vitamin D receptor regulated genes reveals EGFR polymorphism is associated with high-grade serous ovarian cancer in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1289. doi:10.1158/1538-7445.AM2017-1289

Common Variants in TRDN and CALM1 Are Associated with Risk of Sudden Cardiac Death in Chronic Heart Failure Patients in Chinese Han Population.

BackgroundRecent studies suggest that variants in two calcium handling genes (RyR2 and CASQ2) associated with sudden cardiac death (SCD) and non-sudden cardiac death (NSCD) in subjects with heart failure and coronary artery disease, respectively. The purpose of this study was to identify other calcium handling genes associated with SCD in the long-term of chronic heart failure (CHF) in Chinese Han population.Methods and ResultsWe investigated 20 SNPs representing 10 genes that regulated calcium handling in 1429 patients with CHF, and the genetic association with SCD and all-cause death was analysed. During a median follow-up period of 63 months, 538 patients (37.65%) died from CHF, of whom 185 (34.38%) had SCD and the others were NSCD. SNPs that pass a P value cut-off of 0.0025 were considered as significant. We found that patients carrying the CC genotype of rs3814843 on CALM1 gene had greater risks of SCD (HR 5.542, 95% CI 2.054–14.948, P = .001) and all cause death (HR 3.484, 95% CI 1.651–7.350, P = .001). After adjusting for other risk factors, significant associations remained. Moreover, patients carrying G allele of rs361508 on TRDN gene also had increased risk of SCD.ConclusionsCommon variants in TRDN and CALM1 are associated with increased risk of SCD in patients with CHF. These findings provide further evidence for association of variants in calcium handling regulating proteins and SCD in chronic heart failure.

Interferons in Sjögren’s Syndrome: Genes, Mechanisms, and Effects

Sjögren’s syndrome (SS) is a common, progressive autoimmune exocrinopathy distinguished by dry eyes and mouth and affects ∼0.7% of the European population. Overexpression of transcripts induced by interferons (IFN), termed as an “IFN signature,” has been found in SS patients. Four microarray studies have been published in SS that identified dysregulated genes within type I IFN signaling in either salivary glands or peripheral blood of SS patients. The mechanism of this type I IFN activation is still obscure, but several possible explanations have been proposed, including virus infection-initiated and immune complex-initiated type I IFN production by plasmacytoid dendritic cells. Genetic predisposition to increased type I IFN signaling is supported by candidate gene studies showing evidence for association of variants within IFN-related genes. Once activated, IFN signaling may contribute to numerous aspects of SS pathophysiology, including lymphocyte infiltration into exocrine glands, autoantibody production, and glandular cell apoptosis. Thus, dysregulation of IFN pathways is an important feature that can be potentially used as a serum biomarker for diagnosis and targeting of new treatments in this complex autoimmune disease.

Variants in the human potassium channel gene (KCNN3) are associated with migraine in a high risk genetic isolate

The calcium-activated potassium ion channel gene (KCNN3) is located in the vicinity of the familial hemiplegic migraine type 2 locus on chromosome 1q21.3. This gene is expressed in the central nervous system and plays a role in neural excitability. Previous association studies have provided some, although not conclusive, evidence for involvement of this gene in migraine susceptibility. To elucidate KCNN3 involvement in migraine, we performed gene-wide SNP genotyping in a high-risk genetic isolate from Norfolk Island, a population descended from a small number of eighteenth century Isle of Man ‘Bounty Mutineer’ and Tahitian founders. Phenotype information was available for 377 individuals who are related through the single, well-defined Norfolk pedigree (96 were affected: 64 MA, 32 MO). A total of 85 SNPs spanning the KCNN3 gene were genotyped in a sub-sample of 285 related individuals (76 affected), all core members of the extensive Norfolk Island ‘Bounty Mutineer’ genealogy. All genotyping was performed using the Illumina BeadArray platform. The analysis was performed using the statistical program SOLAR v4.0.6 assuming an additive model of allelic effect adjusted for the effects of age and sex. Haplotype analysis was undertaken using the program HAPLOVIEW v4.0. A total of four intronic SNPs in the KCNN3 gene displayed significant association (P < 0.05) with migraine. Two SNPs, rs73532286 and rs6426929, separated by approximately 0.1 kb, displayed complete LD (r 2 = 1.00, D′ = 1.00, D′ 95% CI = 0.96–1.00). In all cases, the minor allele led to a decrease in migraine risk (beta coefficient = 0.286–0.315), suggesting that common gene variants confer an increased risk of migraine in the Norfolk pedigree. This effect may be explained by founder effect in this genetic isolate. This study provides evidence for association of variants in the KCNN3 ion channel gene with migraine susceptibility in the Norfolk genetic isolate with the rarer allelic variants conferring a possible protective role. This the first comprehensive analysis of this potential candidate gene in migraine and also the first study that has utilised the unique Norfolk Island large pedigree isolate to implicate a specific migraine gene. Studies of additional variants in KCNN3 in the Norfolk pedigree are now required (e.g. polyglutamine variants) and further analyses in other population data sets are required to clarify the association of the KCNN3 gene and migraine risk in the general outbred population.

Confirmation of Genetic Associations at ELMO1 in the GoKinD Collection Supports Its Role as a Susceptibility Gene in Diabetic Nephropathy

OBJECTIVETo examine the association between single nucleotide polymorphisms (SNPs) in the engulfment and cell motility 1 (ELMO1) gene, a locus previously shown to be associated with diabetic nephropathy in two ethnically distinct type 2 diabetic populations, and the risk of nephropathy in type 1 diabetes.RESEARCH DESIGN AND METHODSGenotypic data from a genome-wide association scan (GWAS) of the Genetics of Kidneys in Diabetes (GoKinD) study collection were analyzed for associations across the ELMO1 locus. In total, genetic associations were assessed using 118 SNPs and 1,705 individuals of European ancestry with type 1 diabetes (885 normoalbuminuric control subjects and 820 advanced diabetic nephropathy case subjects).RESULTSThe strongest associations in ELMO1 occurred at rs11769038 (odds ratio [OR] 1.24; P = 1.7 × 10−3) and rs1882080 (OR 1.23; P = 3.2 × 10−3) located in intron 16. Two additional SNPs, located in introns 18 and 20, respectively, were also associated with diabetic nephropathy. No evidence of association for variants previously reported in type 2 diabetes was observed in our collection.CONCLUSIONSUsing GWAS data from the GoKinD collection, we comprehensively examined evidence of association across the ELMO1 locus. Our investigation marks the third report of associations in ELMO1 with diabetic nephropathy, further establishing its role in the susceptibility of this disease. There is evidence of allelic heterogeneity, contributed by the diverse genetic backgrounds of the different ethnic groups examined. Further investigation of SNPs at this locus is necessary to fully understand the commonality of these associations and the mechanism(s) underlying their role in diabetic nephropathy.

Family-based association of YWHAH in psychotic bipolar disorder.

YWHAH is a positional and functional candidate gene for both schizophrenia and bipolar disorder (BP). This gene has been previously shown to be associated with both disorders, and the chromosome location (22q12.3) has been repeatedly implicated in linkage studies for these disorders. It codes for the eta subtype of the 14-3-3 protein family, is expressed mainly in brain, and is involved in HPA axis regulation. We investigated the association of YWHAH with BP in a large sample, consisting of 1211 subjects from 318 nuclear families including 554 affected offspring. We tested for association with the standard BP phenotype as well as subtypes defined by psychotic and mood-incongruent features. We genotyped five tag SNPs and the (GCCTGCA)(n) polymorphic locus present in this gene. Using a family-based association test, we found that rs2246704 was associated with BP (OR 1.31, P = 0.03) and psychotic BP (OR = 1.66, P = 0.002). The polymorphic repeat and two other SNPs were also modestly associated with psychotic BP. We have provided additional evidence for association of variants in YWHAH with major mental illness. Additional association analyses of larger sample sets will be required to clarify the role of YWHAH in schizophrenia and BP. The use of clinical sub-phenotypes such as psychotic features or other potential schizophrenia/BP overlap variables including cognitive abnormalities and poor functioning might shed further light on the potential subtypes of illness most closely associated with genetic variation in YWHAH.

Variants in the ATM gene and breast cancer susceptibility

It has been established that heterozygous carriers of ataxia-telangiectasia-causing mutations in the ATM gene are at approximately two-fold higher risk of breast cancer. Several studies have attempted to assess the potential implication of the gene's more common variants in breast cancer susceptibility. Three large case-control studies have consistently found no evidence of association for variants with minor allele frequency greater than 5%. Other studies have evaluated associations for coding variants with intermediate frequency (1-5%), but the results are inconsistent. Larger and/or combined association studies are needed to clarify this issue.

Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility

Rheumatoid arthritis (RA) is an archetypal, common, complex autoimmune disease with both genetic and environmental contributions to disease aetiology. Two novel RA susceptibility loci have been reported from recent genome-wide and candidate gene association studies. We, therefore, investigated the evidence for association of the STAT4 and TRAF1/C5 loci with RA using imputed data from the Wellcome Trust Case Control Consortium (WTCCC). No evidence for association of variants mapping to the TRAF1/C5 gene was detected in the 1860 RA cases and 2930 control samples tested in that study. Variants mapping to the STAT4 gene did show evidence for association (rs7574865, P = 0.04). Given the association of the TRAF1/C5 locus in two previous large case–control series from populations of European descent and the evidence for association of the STAT4 locus in the WTCCC study, single nucleotide polymorphisms mapping to these loci were tested for association with RA in an independent UK series comprising DNA from >3000 cases with disease and >3000 controls and a combined analysis including the WTCCC data was undertaken. We confirm association of the STAT4 and the TRAF1/C5 loci with RA bringing to 5 the number of confirmed susceptibility loci. The effect sizes are less than those reported previously but are likely to be a more accurate reflection of the true effect size given the larger size of the cohort investigated in the current study.

Tagging Single-Nucleotide Polymorphisms in Antioxidant Defense Enzymes and Susceptibility to Breast Cancer

It is generally believed that the initiation of breast cancer is a consequence of cumulative genetic damage leading to genetic alterations and provoking uncontrolled cellular proliferation and/or aberrant programmed cell death, or apoptosis. Reactive oxygen species have been related to the etiology of cancer as they are known to be mitogenic and therefore capable of tumor promotion. The aim of this study was to assess the role of common variation in 10 polymorphic genes coding for antioxidant defense enzymes in modulating individual susceptibility to breast cancer using a case-control study (N cases = 4,474 and N controls = 4,580). Both cases and controls were from the East Anglian region of the United Kingdom. We have identified a set of 54 single nucleotide polymorphisms (SNPs) that efficiently tag all the known SNPs in the 10 genes and are also expected to tag any unknown SNPs in each gene. We found no evidence for association of common variants in SOD1, SOD2, GPX1, GPX4, GSR, TXNRD1, and TXN2. There was borderline evidence for association of variants in CAT g27168a {P [2 degrees of freedom (df)] = 0.05}, TXN t2715c [P (2 df) = 0.007], and TXNRD2 A66S and TXNRD2 g23524a (P(trend) = 0.074 and 0.046, respectively). For TXNRD2 A66S [AS versus AA: odds ratio (OR), 1.05; 95% confidence intervals (95% CI), 0.96-1.15; SS versus AA: OR, 1.12; 95% CI, 0.98-1.29], there are bioinformatics data to suggest that it is functional but confirmation in independent data sets is required before they can be regarded as definitive breast cancer susceptibility alleles. Even if confirmed, these four alleles would account for just 0.32% of the excess familial risk of breast cancer.

Further Evidence for Association of Variants in the AKT1 Gene with Schizophrenia in a Sample of European Sib-Pair Families

Involvement of AKT signaling pathways in schizophrenia has been recently suggested, on the basis of several lines of evidence. In addition to impairment of protein-levels and phosphorylation levels in the pathway, association of DNA sequence variants in the AKT1 gene with schizophrenia has been detected in a family sample. We investigated the reported association of DNA sequence variants in the AKT1 gene in a sample of 79 sib-pair families with schizophrenia using the five single nucleotide polymorphisms (SNPs) of the original study and two additional SNPs in the neighborhood of the SNP for which association had been reported. We obtained statistical significance for single markers (p = .002) and multilocus haplotypes (p = .0013) located in the same region as has been reported in the previous study. The replication of association of variants in the AKT1 gene in a family sample with similar ethnical background as in the original study adds further evidence for involvement of AKT1 in development of schizophrenic disorders.