Genome-wide association study of response to cognitive behavioural therapy in children with anxiety disorders

Background Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. Aims To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980). Method Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. Results No variants passed a genome-wide significance threshold (P = 5×10−8) in either analysis. Four variants met criteria for suggestive significance (P<5×10−6) in association with response post-treatment, and three variants in the 6-month follow-up analysis. Conclusions This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.

Genome - wide association study identifies novel breast cancer susceptibility loci

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r² > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10^-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.

Analysis of genome-wide association study data using the protein knowledge base

Article 98

Candidate disease gene prediction using Gentrepid: application to a genome-wide association study on coronary artery disease

Current single-locus-based analyses and candidate disease gene prediction methodologies used in genome-wide association studies (GWAS) do not capitalize on the wealth of the underlying genetic data, nor functional data available from molecular biology. Here, we analyzed GWAS data from the Wellcome Trust Case Control Consortium (WTCCC) on coronary artery disease (CAD). Gentrepid uses a multiple-locus-based approach, drawing on protein pathway- or domain-based data to make predictions. Known disease genes may be used as additional information (seeded method) or predictions can be based entirely on GWAS single nucleotide polymorphisms (SNPs) (ab initio method). We looked in detail at specific predictions made by Gentrepid for CAD and compared these with known genetic data and the scientific literature. Gentrepid was able to extract known disease genes from the candidate search space and predict plausible novel disease genes from both known and novel WTCCC-implicated loci. The disease gene candidates are consistent with known biological information. The results demonstrate that this computational approach is feasible and a valuable discovery tool for geneticists.

Novel therapeutics for cononary artery disease from genome-wide association study data

Abstract
Background: Coronary artery disease (CAD), one of the leading causes of death globally, is influenced by both environmental and genetic risk factors. Gene-centric genome-wide association studies (GWAS) involving cases and controls have been remarkably successful in identifying genetic loci contributing to CAD. Modern in silico platforms, such as candidate gene prediction tools, permit a systematic analysis of GWAS data to identify candidate genes for complex diseases like CAD. Subsequent integration of drug-target data from drug databases with the predicted candidate genes can potentially identify novel therapeutics suitable for repositioning towards treatment of CAD.
Methods: Previously, we were able to predict 264 candidate genes and 104 potential therapeutic targets for CAD using Gentrepid (www.gentrepid.org), a candidate gene prediction platform with two bioinformatic modules to reanalyze Wellcome Trust Case-Control Consortium GWAS data. In an expanded study, using five bioinformatics modules on the same data, Gentrepid predicted 647 candidate genes and successfully replicated 55% of the candidate genes identified by the more powerful CARDIoGRAMplusC4D consortium meta-analysis. Hence, Gentrepid was capable of enhancing lower quality genotype-phenotype data, using an independent knowledgebase of existing biological data. Here, we used our methodology to integrate drug data from three drug databases: the Therapeutic Target Database, PharmGKB and Drug Bank, with the 647 candidate gene predictions from Gentrepid. We utilized known CAD targets, the scientific literature, existing drug data and the CARDIoGRAMplusC4D meta-analysis study as benchmarks to validate Gentrepid predictions for CAD.
Results: Our analysis identified a total of 184 predicted candidate genes as novel therapeutic targets for CAD, and 981 novel therapeutics feasible for repositioning in clinical trials towards treatment of CAD. The benchmarks based on known CAD targets and the scientific literature showed that our results were significant (p < 0.05).
Conclusions: We have demonstrated that available drugs may potentially be repositioned as novel therapeutics for the treatment of CAD. Drug repositioning can save valuable time and money spent on preclinical and phase I clinical studies.

Genetic association between body composition measured by ultrasound and visual scores in Brazilian Nelore cattle

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Genome-wide association study for backfat thickness in Canchim beef cattle using Random Forest approach

Background: Meat quality involves many traits, such as marbling, tenderness, juiciness, and backfat thickness, all of which require attention from livestock producers. Backfat thickness improvement by means of traditional selection techniques in Canchim beef cattle has been challenging due to its low heritability, and it is measured late in an animal's life. Therefore, the implementation of new methodologies for identification of single nucleotide polymorphisms (SNPs) linked to backfat thickness are an important strategy for genetic improvement of carcass and meat quality.Results: The set of SNPs identified by the random forest approach explained as much as 50% of the deregressed estimated breeding value (dEBV) variance associated with backfat thickness, and a small set of 5 SNPs were able to explain 34% of the dEBV for backfat thickness. Several quantitative trait loci (QTL) for fat-related traits were found in the surrounding areas of the SNPs, as well as many genes with roles in lipid metabolism.Conclusions: These results provided a better understanding of the backfat deposition and regulation pathways, and can be considered a starting point for future implementation of a genomic selection program for backfat thickness in Canchim beef cattle. © 2013 Mokry et al.; licensee BioMed Central Ltd.

Genome-wide association study for birth weight in Nellore cattle points to previously described orthologous genes affecting human and bovine height

Background: Birth weight (BW) is an economically important trait in beef cattle, and is associated with growth- and stature-related traits and calving difficulty. One region of the cattle genome, located on Bos primigenius taurus chromosome 14 (BTA14), has been previously shown to be associated with stature by multiple independent studies, and contains orthologous genes affecting human height. A genome-wide association study (GWAS) for BW in Brazilian Nellore cattle (Bos primigenius indicus) was performed using estimated breeding values (EBVs) of 654 progeny-tested bulls genotyped for over 777,000 single nucleotide polymorphisms (SNPs).Results: The most significant SNP (rs133012258, PGC = 1.34 × 10-9), located at BTA14:25376827, explained 4.62% of the variance in BW EBVs. The surrounding 1 Mb region presented high identity with human, pig and mouse autosomes 8, 4 and 4, respectively, and contains the orthologous height genes PLAG1, CHCHD7, MOS, RPS20, LYN, RDHE2 (SDR16C5) and PENK. The region also overlapped 28 quantitative trait loci (QTLs) previously reported in literature by linkage mapping studies in cattle, including QTLs for birth weight, mature height, carcass weight, stature, pre-weaning average daily gain, calving ease, and gestation length.Conclusions: This study presents the first GWAS applying a high-density SNP panel to identify putative chromosome regions affecting birth weight in Nellore cattle. These results suggest that the QTLs on BTA14 associated with body size in taurine cattle (Bos primigenius taurus) also affect birth weight and size in zebu cattle (Bos primigenius indicus). © 2013 Utsunomiya et al.; licensee BioMed Central Ltd.

Genetic association between milk yield, stayability, and mastitis in Holstein cows under tropical conditions

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Genome-wide association study of reproduction traits in Nelore cattle, including additional phenotypic information from non-genotyped animals

Pós-graduação em Genética e Melhoramento Animal - FCAV

Genome-wide association study and ancestral origins of the slick-hair coat in tropically adapted cattle

The slick hair coat (SLICK) is a dominantly inherited trait typically associated with tropically adapted cattle that are from Criollo descent through Spanish colonization of cattle into the New World. The trait is of interest relative to climate change, due to its association with improved thermo-tolerance and subsequent increased productivity. Previous studies localized the SLICK locus to a 4 cM region on chromosome (BTA) 20 and identified signatures of selection in this region derived from Senepol cattle. The current study compares three slick-haired Criollo-derived breeds including Senepol, Carora, and Romosinuano and three additional slick-haired cross-bred lineages to non-slick ancestral breeds. Genome-wide association (GWA), haplotype analysis, signatures of selection, runs of homozygosity (ROH), and identity by state (IBS) calculations were used to identify a 0.8 Mb (37.7-38.5 Mb) consensus region for the SLICK locus on BTA20 in which contains SKP2 and SPEF2 as possible candidate genes. Three specific haplotype patterns are identified in slick individuals, all with zero frequency in non-slick individuals. Admixture analysis identified common genetic patterns between the three slick breeds at the SLICK locus. Principal component analysis (PCA) and admixture results show Senepol and Romosinuano sharing a higher degree of genetic similarity to one another with a much lesser degree of similarity to Carora. Variation in GWA, haplotype analysis, and IBS calculations with accompanying population structure information supports potentially two mutations, one common to Senepol and Romosinuano and another in Carora, effecting genes contained within our refined location for the SLICK locus.

Genome-wide association study of reproductive traits in Nellore heifers using Bayesian inference

An important goal of Zebu breeding programs is to improve reproductive performance. A major problem faced with the genetic improvement of reproductive traits is that recording the time for an animal to reach sexual maturity is costly. Another issue is that accurate estimates of breeding values are obtained only a long time after the young bulls have gone through selection. An alternative to overcome these problems is to use traits that are indicators of the reproductive efficiency of the herd and are easier to measure, such as age at first calving. Another problem is that heifers that have conceived once may fail to conceive in the next breeding season, which increases production costs. Thus, increasing heifer's rebreeding rates should improve the economic efficiency of the herd. Response to selection for these traits tends to be slow, since they have a low heritability and phenotypic information is provided only later in the life of the animal. Genome-wide association studies (GWAS) are useful to investigate the genetic mechanisms that underlie these traits by identifying the genes and metabolic pathways involved. Data from 1853 females belonging to the Agricultural Jacarezinho LTDA were used. Genotyping was performed using the BovineHD BeadChip (777 962 single nucleotide polymorphisms (SNPs)) according to the protocol of Illumina - Infinium Assay II ® Multi-Sample HiScan with the unit SQ ™ System. After quality control, 305 348 SNPs were used for GWAS. Forty-two and 19 SNPs had a Bayes factor greater than 150 for heifer rebreeding and age at first calving, respectively. All significant SNPs for age at first calving were significant for heifer rebreeding. These 42 SNPs were next or within 35 genes that were distributed over 18 chromosomes and comprised 27 protein-encoding genes, six pseudogenes and two miscellaneous noncoding RNAs. The use of Bayes factor to determine the significance of SNPs allowed us to identify two sets of 42 and 19 significant SNPs for heifer rebreeding and age at first calving, respectively, which explain 11.35 % and 6.42 % of their phenotypic variance, respectively. These SNPs provide relevant information to help elucidate which genes affect these traits.

Association study between functional polymorphisms in the TNF-alpha gene and obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a prevalent psychiatric disorder of unknown etiology. However, there is some evidence that the immune system may play an important role in its pathogenesis. In the present study, two polymorphisms (rs1800795 and rs361525) in the promoter region of the cytokine tumor necrosis factor-alpha (TNFA) gene were genotyped in 183 OCD patients and in 249 healthy controls. The statistical tests were performed using the PLINK (R) software. We found that the A allele of the TNFA rs361525 polymorphism was significantly associated with OCD subjects, according to the allelic x association test (p=0.007). The presence of genetic markers, such as inflammatory cytokines genes linked to OCD, may represent additional evidence supporting the rote of the immune system in its pathogenesis.

Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.