Investigation of gene-environment interactions in relation to tic severity

Association of CAV1/CAV2 Genomic Variants with Primary Open-Angle Glaucoma Overall and by Gender and Pattern of Visual Field Loss

Analysis of PTPRK polymorphisms in association with risk and age at onset of Alzheimer's disease, cancer risk, and cholesterol

Aims/hypothesis: Genome-wide association studies have identified over 50 new genetic loci for type 2 diabetes (T2D). Several studies conclude that higher dietary heme iron intake increases the risk of T2D. Therefore we assessed whether the relation between genetic loci and T2D is modified by dietary heme iron intake.Methods: We used Affymetrix Genome-Wide Human 6.0 array data [681,770 single nucleotide polymorphisms (SNPs)] and dietary information collected in the Health Professionals Follow-up Study (n = 725 cases; n = 1,273 controls) and the Nurses’ Health Study (n = 1,081 cases; n = 1,692 controls). We assessed whether genome-wide SNPs or iron metabolism SNPs interacted with dietary heme iron intake in relation to T2D, testing for associations in each cohort separately and then meta-analyzing to pool the results. Finally, we created 1,000 synthetic pathways matched to an iron metabolism pathway on number of genes, and number of SNPs in each gene. We compared the iron metabolic pathway SNPs with these synthetic SNP assemblies in their relation to T2D to assess if the pathway as a whole interacts with dietary heme iron intake.Results: Using a genomic approach, we found no significant gene–environment interactions with dietary heme iron intake in relation to T2D at a Bonferroni corrected genome-wide significance level of 7.33 ×10-8 (top SNP in pooled analysis: intergenic rs10980508; p = 1.03 × 10-6). Furthermore, no SNP in the iron metabolic pathway significantly interacted with dietary heme iron intake at a Bonferroni corrected significance level of 2.10 × 10-4 (top SNP in pooled analysis: rs1805313; p = 1.14 × 10-3). Finally, neither the main genetic effects (pooled empirical p by SNP = 0.41), nor gene – dietary heme–iron interactions (pooled empirical p-value for the interactions = 0.72) were significant for the iron metabolic pathway as a whole.Conclusions: We found no significant interactions between dietary heme iron intake and common SNPs in relation to T2D.

<div>Abstract<p><b>Purpose:</b> Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate single nucleotide polymorphisms (SNP)/genes, we carried out a genome-wide association study (GWAS) for cisplatin cytotoxicity by using lymphoblastoid cell lines (LCL), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients.</p><p><b>Experimental Design:</b> A GWAS for cisplatin was conducted with 283 ethnically diverse LCLs. A total of 168 top SNPs were genotyped in 222 small cell lung cancer (SCLC) and 961 non-SCLC (NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined by using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells.</p><p><b>Results:</b> Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the 4 top SNPs and 8 genes for which expression was correlated with 3 SNPs in LCLs were selected for siRNA screening. Knockdown of <i>DAPK3</i> and <i>METTL6</i>, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells.</p><p><b>Conclusions:</b> This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer. <i>Clin Cancer Res; 17(17); 5801–11. ©2011 AACR</i>.</p></div>

Implication of Inherited Genetic Variants Associated with Follicular Lymphoma Susceptibility in the Prognosis of Patients Treated By Immunochemotherapy in PRIMA Study

Sensory hypersensitivity in Tourette syndrome: A review

Patients with Gilles de la Tourette syndrome have widespread personality differences

Antituberculosis drug-induced liver injury (ATDILI) is a common side effect leading to tuberculosis (TB) treatment disruption. The mechanism of the disease remains poorly understood. We conducted a genomewide association study (GWAS) to investigate all possible genetic factors of ATDILI in Thai patients. This study was carried out in Thai TB patients, including 79 ATDILI cases and 239 tolerant controls from our network hospitals in Thailand. Nearly 1 million single-nucleotide polymorphisms (SNPs) were genotyped across the whole genome using an Illumina OmniExpress Exome BeadChip array. In the discovery stage, we identified strong association signals on chromosome 8 originating from the N-acetyltransferase (NAT2) region. The A allele of rs1495741, the top SNP in the intergenic region of NAT2 and PSD3 (14 kb from NAT2), was significantly associated with ATDILI (recessive model, odds ratio of 6.01 [95% confidence interval, 3.42 to 10.57]; P = 6.86E-11). This particular SNP was reported as a tag SNP for NAT2 inferred phenotypes. The AA, AG, and GG genotypes represented NAT2 slow acetylators, intermediate acetylators, and fast acetylators, respectively. The tag SNP genotypes demonstrated a concordance rate of 94.98% with NAT2 acetylator phenotypes. This GWAS shows that NAT2 is the most important risk factor for ATDILI in the Thai population.

Tourette syndrome is often associated with attention deficit hyperactivity disorder, obsessive compulsive disorder and other co-morbidities, the presence of which can reduce health-related quality of life. The relationship between the number and type of co-morbidities and tic severity upon health-related quality of life has been insufficiently examined in Tourette syndrome populations and not at all in the Australian context. We hypothesised that an increased number of co-morbid diagnoses would be inversely related to health-related quality of life and that the presence of attention deficit hyperactivity disorder and obsessive compulsive disorder in particular would negatively impact health-related quality of life. In all, 83 people with a previously established diagnosis of Tourette syndrome, who responded to a letter of invitation sent to the Tourette Syndrome Association of Australia past-member database, formed the study sample. Participants completed the Gilles de la Tourette Syndrome-Quality of Life Scale and a short form of the National Hospital Interview Schedule to assess tics and related behaviours. Participants with pure-Tourette syndrome had significantly better health-related quality of life than those with Tourette syndrome and three or more co-morbid diagnoses. Few differences were observed between the pure-Tourette syndrome and Tourette syndrome and one or two co-morbid diagnoses groups. Analysis of the impact of individual co-morbid disorders and Tourette syndrome symptoms on health-related quality of life indicated that attention deficit hyperactivity disorder exerted a significant negative effect, as did the presence of complex tics, especially coprolalia and copropraxia. When these variables were examined in multiple regression analysis, number of co-morbidities and the presence of coprophenomena emerged as significant predictors of health-related quality of life. While tics are the defining feature of Tourette syndrome, it appears to be the presence of co-morbidities, attention deficit hyperactivity disorder, in particular, and coprophenomena that have the greater impact on health-related quality of life. This has implications for symptom-targeting in the treatment of Tourette syndrome since all available treatments are symptomatic and not disease modifying.

Neoadjuvant chemotherapy (NAC) for breast cancer is widely utilized, and we performed genome-wide association studies (GWAS) to determine whether germ-line genetic variability was associated with benefit in terms of pathological complete response (pCR), disease-free survival, and overall survival in patients entered on the NSABP B-40 NAC trial, wherein patients were randomized to receive, or not, bevacizumab in addition to chemotherapy. Patient DNA samples were genotyped with the Illumina OmniExpress BeadChip. Replication was attempted with genotyping data from 1398 HER2-negative patients entered on the GeparQuinto NAC study in which patients were also randomized to receive, or not, bevacizumab in addition to chemotherapy. A total of 920 women from B-40 were analyzed, and 237 patients achieved a pCR. GWAS with three phenotypes (pCR, disease-free survival, overall survival) revealed no single nucleotide polymorphisms (SNPs) that were genome-wide significant (i.e. P≤5E-08) signals; P values for top SNPs were 2.04E-07, 5.61E-08, and 5.63E-08, respectively, and these SNPs were not significant in the GeparQuinto data. An ad-hoc GWAS was performed in the patients randomized to bevacizumab (457 patients with 128 pCR) who showed signals on chromosome 6, located within a gene, CDKAL1, that approached, but did not reach, genome-wide significance (top SNP rs7453577, P=2.97E-07). However, this finding was significant when tested in the GeparQuinto data set (P=0.04). In conclusion, we identified no SNPs significantly associated with NAC. The observation, in a hypothesis-generating GWAS, of an SNP in CDKAL1 associated with pCR in the bevacizumab arm of both B-40 and GeparQuinto requires further validation and study.

OBJECTIVEDiabetic nephropathy and retinopathy are two important microvascular diabetes complications with a high concordance rate in diabetic patients. A recent genome-wide association study in type 1 diabetic patients of European descent identified four loci to be associated with diabetic nephropathy. The aim of this study was to test the effects of single nucleotide polymorphisms (SNPs) from these four loci on diabetic nephropathy and retinopathy in Chinese type 2 diabetic patients.RESEARCH DESIGN AND METHODSIn stage 1, we recruited 1,276 type 2 diabetic patients, including 378 patients with diabetic nephropathy but no retinopathy, 374 patients with diabetic retinopathy but no nephropathy, 244 patients with both diabetic retinopathy and nephropathy, and 280 control subjects with diabetes for >10 years and no diabetic retinopathy or nephropathy. Fifty-five SNPs from four loci (CPVL/CHN2, FRMD3, CARS, and IRS2) were genotyped. The SNPs that showed associations to diabetic retinopathy or nephropathy were genotyped in stage 2 samples for replication.RESULTSSNPs from CPVL/CHN2 and FRMD3 were associated with diabetic retinopathy with rs39059 and rs10868025 as the top SNPs (odds ratio [OR] 1.292, 95% CI 1.097–1.523, P = 0.0022, for rs39059; 1.201, 1.014–1.422, P = 0.0343, for rs10868025) in stage 1 samples. In stage 2 analysis, only rs39059 showed similar effect to diabetic retinopathy (OR 1.269, 0.989–1.628, P = 0.0689), and meta-analysis showed a significant association between rs39059 and diabetic retinopathy, with an OR of 1.285 (1.120–1.474, P = 0.0003). CPVL/CHN2 rs39059 was also associated with levels of diabetic retinopathy (P = 0.0007 for trend). However, no association was detected between these SNPs and diabetic nephropathy.CONCLUSIONSIn this study, we found CPVL/CHN2 rs39059 was associated with diabetic retinopathy in the Chinese type 2 diabetic patients.

BackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). CTE has distinct neuropathology defined by perivascular hyperphosphorylated tau (ptau) deposition. The presence and severity of CTE pathology varies among those with similar RHI exposure, suggesting a role for non‐RHI risk factors, including genetics. Here we conducted the first genome‐wide association study (GWAS) of neuropathologically‐confirmed CTE.Method175 brain donors from the Veterans Affairs‐Boston University‐Concussion Legacy Foundation Brain Bank with known exposure to RHI in the form of contact sports and/or military service were assessed for CTE pathology. CTE pathology was staged on a semiquantitative scale from 0 to 4 (0 = absent; 4 = most severe). Ptau burden was also assessed across 11 brain regions commonly affected in CTE on a semiquantitative scale from 0 to 3 (0 = absent; 3 = most severe). We tested the association of genome‐wide genotyped and imputed single nucleotide polymorphisms (SNPs) with CTE stage in a linear regression model adjusted for 10 principal components of population substructure. We tested the association of top hits with ptau burden in each of the 11 brain regions.ResultTwo loci achieved genome‐wide significance: top SNP rs63565460 [minor allele frequency (MAF) = 0.08; beta = ‐1.64; p = 2.4 × 10−8] is an intronic SNP in PIP5K1B on chromosome 9; and top SNP rs12447028 (MAF = 0.07; beta = ‐1.84, p = 2.6 × 10−8) is an intronic SNP in ABAT on chromosome 16. The PIP5K1B locus had the largest effects in cortical regions. PIP5K1B is expressed in brain and has been associated with intelligence in GWAS. The ABAT locus had the largest effects in the inferior orbital gyrus and the locus coeruleus. ABAT is expressed in brain and has been associated in GWAS with anger proclivity, a symptom of CTE. The ABAT protein functions in GABA catabolism.ConclusionIn the first GWAS of CTE, two promising loci in PIP5K1B and ABAT achieved genome‐wide significance. Both loci had the largest effects in brain regions affected early in CTE. Efforts to enlarge the sample size, incorporate measures of RHI exposure and test additional endophenotypes are underway. Identified loci may implicate disease mechanisms, provide targets for therapies, and guide counseling of athletes regarding risk of play.

Schizophrenia is a chronic and debilitating psychiatric condition affecting slightly more than 1% of the population worldwide and it is a multifactorial disorder with a high degree of heritability (80%) based on family and twin studies. Increasing lines of evidence suggest intermediate phenotypes/endophenotypes are more associated with causes of the disease and are less genetically complex than the broader disease spectrum. Negative symptoms in schizophrenia are attractive intermediate phenotypes based on their clinical and treatment response features. Therefore, our objective was to identify genetic variants underlying the negative symptoms of schizophrenia by analyzing two genome-wide association (GWA) data sets consisting of a total of 1,774 European-American patients and 2,726 controls. Logistic regression analysis of negative symptoms as a binary trait (adjusted for age and sex) was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 25 single nucleotide polymorphisms (SNPs) associated with negative symptoms with p<5×10−5. Especially we detected five SNPs in the first two genes/loci strongly associated with negative symptoms of schizophrenia (Pmeta-analysis<6.22×10−6), which included three SNPs in the BCL9 gene: rs583583 showed the strongest association at a Pmeta-analysis of 6.00×10−7 and two SNPs in the C9orf5 (the top SNP is rs643410 with a p = 1.29 ×10−6). Through meta-analysis, we identified several additional negative symptoms associated genes (ST3GAL1, RNF144, CTNNA3 and ZNF385D). This is the first report of the common variants influencing negative symptoms of schizophrenia. These results provide direct evidence of using of negative symptoms as an intermediate phenotype to dissect the complex genetics of schizophrenia. However, additional studies are warranted to examine the underlying mechanisms of these disease-associated SNPs in these genes.

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two highly heritable neurodevelopmental disorders. Several lines of evidence point towards the presence of shared genetic factors underlying ASD and ADHD. We conducted genomic analyses of common risk variants (i.e. single nucleotide polymorphisms, SNPs) shared by ASD and ADHD, and those specific to each disorder. With the summary data from two GWAS, one on ASD (N=46,350) and another on ADHD (N=55,374) individuals, we used genomic structural equationmodelling and colocalization analysis to identify SNPs shared by ASD and ADHD and SNPs specific to each disorder. Functional genomic analyses were then conducted on shared and specific common genetic variants. Finally, we performed a bidirectional Mendelian randomization analysis to test whether the shared genetic risk between ASD and ADHD was interpretable in terms of reciprocal relationships between ASD and ADHD. We found that 37.5% of the SNPs associated with ASD (at p<1e-6) colocalized with ADHD SNPs and that 19.6% of the SNPs associated with ADHD colocalized with ASD SNPs. We identified genes mapped to SNPs that are specific to ASD or ADHD and that are shared by ASD and ADHD, including two novel genes INSM1 and PAX1. Our bidirectional Mendelian randomization analyses indicated that the risk of ASD was associated with an increased risk of ADHD and vice versa. Using multivariate genomic analyses, the present study uncovers shared and specific genetic variants associated with ASD and ADHD. Further functional investigation of genes mapped to those shared variants may help identify pathophysiological pathways and new targets for treatment.

Recent genome-wide association studies and meta-analyses have identified 47 susceptibility loci for ulcerative colitis (UC) in Caucasian populations. A previous genome-wide association study of UC in a Japanese population suggested marginal sharing of susceptibility loci between Caucasian and Asian populations. We performed a genome-wide association studies to identify UC susceptibility loci in a Korean population and further comparative study. We analyzed 581,060 autosomal single-nucleotide polymorphisms (SNPs) in 388 individuals with UC and 739 control subjects in the discovery stage. For the validation, 64 suggestive SNPs were analyzed in an additional 417 affected individuals and 732 control subjects. Three genetic loci were validated for significant association, and all were previously reported in Caucasians including the major histocompatibility complex region (top SNP, rs9271366; P = 1.03 × 10(-18), odds ratio [OR] = 2.10), 16q24.1 (rs16940186; P = 4.39 × 10(-10), OR = 1.56), and RNF186-OTUD3-PLA2G2E at chromosome arm 1p36.13 (top SNP, rs4654903 in OTUD3; P = 7.43 × 10(-9), OR = 0.64). Although failed to reach genome-wide statistical significance, 2 additional loci previously reported in Caucasians including rs17085007 at chromosome arm 13q12 and JAK2 at chromosome arm 9p24 were significant after Bonferroni correction (P(corrected) = 0.0016 and P(corrected) = 0.0056, respectively). FOS, UBE2L3, the JAK2 gene region, and rs1297265 at chromosome arm 21q21.1 likely play a role in both Crohn's disease and UC. Our data support the biologic significance of the overlapping loci for UC between Caucasian and Korean populations. Our data suggest that genetic associations for UC tend to overlap more extensively among different ethnic groups than those for Crohn's disease, which shows well-established dependence on ethnicity.