Strongest Association Signal Research Articles

PDG45 ENOXAPARIN AND LIVER INJURY: SIGNAL DETECTION USING DATA FROM FDA ADVERSE EVENT REPORTING SYSTEM (FEARS)

Six individual case reports of enoxaparin induced liver injury were published which indicated enoxaparin as a suspected drug that resulted in hepatotoxicity. However, there is no formal pharmacovigilance or epidemiological study which further investigated the association between enoxaparin and liver injury. This study, quantified the association (signal) between enoxaparin and liver injury using data from the US Food and Drug administration adverse event reporting system (FAERS). A data of 15 drugs and adverse drug event was collected from RED BOOK for the year 1993 to 2017 in US. Proportional reporting ratio (PRR) and reporting odds ratio (ROR), Information component (IC) and empirical Bayes geometric mean (EBGM) were applied to measure the association between these drugs and the adverse event, hepatotoxicity. Of the 3,900 co-matching reports between the 15 drugs and hepatotoxicity, enoxaparin was co-matched 850 times. It was the second highest among all anticoagulant drugs in the study following rivaroxaban (1143 times). Enoxaparin had a PRR (95% CI): 2.35 (1.80,3.07); ROR (95% CI): 2.41 (2.23,2.61); IC (95% CI) 1.04 (0.93,1.12) and EBGM (95% CI) 2.06 (1.84,2.23). PRR of at least 2 is defined as signal and a positive IC represents a signal indicating an association between the drug and adverse drug reaction. Moreover, rivaroxaban had a PRR of 0.45 (95% CI: 0.36,0.57), ROR (95%CI) 0.45 (0.42,0.48); IC of -0.70 (-0.80, -0.63) and EBGM of 0.61; (0.56,0.66). The measure of association showed enoxaparin has a higher signal for drug induced liver injury and was statistically significant. On the other hand, there was no evidence for a signal between rivaroxaban and liver injury despite it had the highest drug-adverse event reports. Enoxaparin had a strong association (signal) with liver injury. However, a signal is not a causal association between a drug and adverse event. Therefore, a formal epidemiological study is warranted.

A gene-based recessive diplotype exome scan discovers FGF6, a novel hepcidin-regulating iron-metabolism gene

AbstractStandard analyses applied to genome-wide association data are well designed to detect additive effects of moderate strength. However, the power for standard genome-wide association study (GWAS) analyses to identify effects from recessive diplotypes is not typically high. We proposed and conducted a gene-based compound heterozygosity test to reveal additional genes underlying complex diseases. With this approach applied to iron overload, a strong association signal was identified between the fibroblast growth factor–encoding gene, FGF6, and hemochromatosis in the central Wisconsin population. Functional validation showed that fibroblast growth factor 6 protein (FGF-6) regulates iron homeostasis and induces transcriptional regulation of hepcidin. Moreover, specific identified FGF6 variants differentially impact iron metabolism. In addition, FGF6 downregulation correlated with iron-metabolism dysfunction in systemic sclerosis and cancer cells. Using the recessive diplotype approach revealed a novel susceptibility hemochromatosis gene and has extended our understanding of the mechanisms involved in iron metabolism.

Genome-wide association study of berry-related traits in grape [Vitis vinifera L.] based on genotyping-by-sequencing markers

ABSTRACTDeciphering the genetic control of grape berry traits is crucial for optimizing yield, fruit quality, and consumer acceptability. In this study, an association panel of 179 grape genotypes comprising a mixture of ancient cultivars, landraces, and modern varieties collected worldwide were genotyped with genotyping-by-sequencing using a genome-wide association approach based on 32,311 single-nucleotide polymorphism (SNP) markers. Genome-wide efficient mixed-model association was selected as the optimal statistical model based on the results of known control loci of grape berry color traits. Many of the associated SNPs identified in this study were in accordance with the previous QTL analyses using biparental mapping. The grape skin color locus was found to be associated with a mybA transcription factor on chromosome 2. Two strong and distinct association signals associated with berry development periods were found on chromosome 16. Most candidate genes of the interval were highlighted as receptor-like protein kinase. For berry weight, significant association loci were identified on chromosome 18, as previously known, and on chromosome 19 and chromosome 17, as newly mapped. Berry flesh texture was newly located on chromosome 16; candidate genes in the interval were related to calcium. Berry flavor was determined on chromosome 5. Genomic regions were further investigated to reveal candidate genes. In this work, we identified interesting genetic determinants of grape berry-related traits. The identification of the markers closely associated with these berry traits may be useful for grape molecular breeding.

SU4 - GENOME-WIDE EXAMINATION OF PARENT-OF-ORIGIN EFFECTS IN CHILDREN WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER

Background Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common and most heritable childhood-onset neuropsychiatric disorders, characterized by multifaceted genetics. To date, genetic studies of ADHD focused on additive effects only, explaining just a fraction of its heritability. Thus, we aimed at examining parent of origin effects (POE) together with maternal and additive effects, providing novel insight into the complex genetic architecture of ADHD. Methods We compiled parent-offspring data collected through the Psychiatric Genomics Consortium and the Norwegian Mother and Child Cohort, consisting of 2060 trios and 328 duos. Additional parent-offspring data is being added. ADHD was diagnosed based on DSM-IV, ICD-10 and child behavior checklist. POE, maternal and additive genetic effects are being evaluated using multinomial modelling implemented in EMIM software. We explored our signals in the light of known imprinted genes (POE) and the largest ADHD Genome-Wide Association Study (GWAS) in children (N=17666). Gene based analyses are being performed using MAGMA software. Heritability estimates and genetic correlations of the examined effects are being calculated using LD score regression. Results Our preliminary results indicate the presence of non-additive genetic effects in the development of ADHD. Our preliminary strongest imprinting signal is located in CALD1 locus (rs11980823, effect=0.77, SE=0.14, P=1.21E-07). This gene also revealed strong association signal in the previously reported large-scale childhood ADHD GWAS (rs79846815, P=2.03E-06). CALD1 plays essential an role in nerve regeneration, a function previously implicated in a number of neuropsychiatric disorders. Our preliminary gene-based analyses of the known imprinted genes revealed strong association with TP73 locus (P=0.0034), encoding a transcription factor implicated in disorders of nervous system (e.g. neuroblastoma). Additional hits were noted in the non-coding RNA genes, adding to the recent observations in neuropsychiatric genetics of gene regulation playing a pivotal role in the development of disorders of mental health. Discussion In conclusion, this is the first and the largest genome-wide parent-offspring study in ADHD, exploring its non-additive genetic effects by detecting and distinguishing between POE (imprinting), maternal and child effects. As we increase our sample size, we will provide estimates of such effects as well as those of their heritability and genetic correlations.

Genome-wide association study reveals the locus responsible for microtia in Valle del Belice sheep breed.

Microtia is a congenital deformity of the outer ear with phenotypes varying from a small auricle to total absence (anotia). The genetic basis is still poorly understood, and very few studies have been performed in sheep. Valle del Belice sheep is a breed showing microtia. The aim of this study was to identify the potential genomic regions involved in microtia in sheep. A total of 40 individuals, 20 with microtia and 20 normal, were genotyped with the Illumina OvineSNP50 BeadChip. The comparison among the results from a genome-wide association study, Fisher's exact test and FST analysis revealed a single strong association signal: rs419889303 on chromosome 1, located within intron 3 of the CLRN1 gene. Our study suggests for the first time that this novel candidate gene is responsible for microtia in sheep. Additional analysis based on the sequencing would help confirm our findings and allow for the proposal of a precise genetic basis for microtia in sheep.

Association of ATF5 Gene with Metabolic Syndrome and Insulin Resistance in Mediterranean Populations

Insulin resistance (InsR) characterizes the metabolic syndrome (MetS) for which many genes were involved by GWAS. To further explore genetic susceptibility involving rare SNPs with major effect we genotyped patients from MEDIGENE collection using Affymetrix MEDISCOPE chip. Screening of French, Romanians and Albanians in Italy and Greece (n = 605) for metabolic pathways detected a new SNP associated with MetS in exon 3/4 of ATF5 (activating transcription factor 5) gene (Chr19q13.33). Genuine association was completed by imputation (BEAGLE4.1) at 1000 Genome Project adding new 6 SNPs and submitted to sliding window (SW) procedure for haplotypes detection. The strong association signal was found for rs61742136 with MetS (P < 1.8x10-7, Bonferroni 2.7x10-6, OR 9.37, 95% CI[3.3-26.8]), InsR (P < 0.00049, OR 3.4, 95% CI[1.7-8.4]) and with HOMA index (P < 0.023). Among MetS components, the strongest association concerned high blood pressure (HBP) (P < 2.1x 10-4, OR 4.8, 95% CI[1.8-12.4]) while HDL, TG and obesity were associated with OR < 3. In women, MetS association signal was much stronger with OR 10.9, 95% CI[3.2-36.6] (P < 8.5x10-7). SW detected associated haplotypes between 3 to 8 SNPs, the best value being that of ATGGGGTC haplotype with OR 12.2, 95% CI[3.2-46.65] (P < 1.98 x10-7, Bonferroni 1.13x10-5). Association of rs61742136 was replicated in MEDIGENE cohort (n = 948) with MetS, albeit with P < 2.0x10-3 (Bonferroni 0.026) and solely with low HDL (P < 0.05). Other SNPs were associated with HBP (rs75273180 and rs1152230 with P < 0.03 and 0.04, respectively) and with potential interactions in Haploreg V4 database. Overall fixation index (Fst = 0.001) indicates a minimal differentiation suggesting adaptive selection in Mediterranean populations. This is a first time report of implication of ATF5 in MetS and gives a new insight on its pathogenesis in view of this CREB valine/leucine zipper transcriptional factor in stress-induced anti-apoptosis or neuroprotective effects. Disclosure S. Haydar: None. F. Grigorescu: None. C. Lautier: None. C. Normand: None. J. Hadi: None. M. Vintila: None. M. Gheorghiu: None. A. Fountas: None. A. Tsatsoulis: None. A. Copola: None. D. Lauro: None. D. Ylli: None. A. Ylli: None. L. Brugnara: None. F. Hanzu: None. R. Gomis: None.

Genome-wide association study of lncRNA polymorphisms with bone mineral density.

Recent studies suggested that long noncoding RNAs (lncRNAs) were widely transcribed in the genome, but their potential roles in the genetic complexity of human disorders required further exploration. The purpose of the present study was to explore genetic polymorphisms of lncRNAs associated with bone mineral density (BMD) and its potential value. Based on the lncRNASNP database, 55,906 lncSNPs were selected to conduct a genome-wide association study meta-analysis among 11,140 individuals of seven independent studies for BMDs at femoral neck (FN), lumbar spine, and total hip (HIP). Promising results were replicated in Genetic Factors for Osteoporosis Consortium (GEFOS Sequencing, n=32,965). We found two lncRNA loci that were significantly associated with BMD. MEF2C antisense RNA 1 (MEF2C-AS1) located at 5q14.3 was significantly associated with FN-BMD after Bonferroni correction, and the strongest association signal was detected at rs6894139 (P=3.03 × 10-9 ). LOC100506136 rs6465531 located at 7q21.3 showed significant association with HIP-BMD (P=7.43 × 10-7 ). MEF2C-AS1 rs6894139 was replicated in GEFOS Sequencing with P-value of 1.43 × 10-23 . Our results illustrated the important role of polymorphisms in lncRNAs in determining variations of BMD and provided justification and evidence for subsequent functional studies.

119. Functional Assessment of an Attempted Suicide Risk Locus

We previously conducted an attempted suicide genome-wide association study in subjects with bipolar disorder that generated a strong association signal on 2p25 (5.07 X 10-8). The top SNPs localize to a 10kb region that we now know contains 30 novel putative microRNAs.

Evidence for association of STAT4 and IL12RB2 variants with Myasthenia gravis susceptibility: What is the effect on gene expression in thymus?

Myasthenia gravis (MG) is an autoimmune disease mediated by the presence of autoantibodies that bind mainly to the acetylcholine receptor (AChR) in the neuromuscular junction. In our case-control association study, we analyzed common variants located in genes of the IL12/STAT4 and IL10/STAT3 signaling pathways. A total of 175 sporadic MG patients of Greek descent, positively detected with anti-AChR autoantibodies and 84 ethnically-matched, healthy volunteers were enrolled in the study. Thymus samples were obtained from 16 non-MG individuals for relative gene expression analysis. The strongest signals of association were observed in the cases of rs6679356 between the late-onset MG patients and controls and rs7574865 between early-onset MG and controls. Our investigation of the correlation between the MG-associated variants and the expression levels of each gene in thymus did not result in significant differences.

Association analysis for udder index and milking speed with imputed whole-genome sequence variants in Nordic Holstein cattle

Genome-wide association testing facilitates the identification of genetic variants associated with complex traits. Mapping genes that promote genetic resistance to mastitis could reduce the cost of antibiotic use and enhance animal welfare and milk production by improving outcomes of breeding for udder health. Using imputed whole-genome sequence variants, we carried out association studies for 2 traits related to udder health, udder index, and milking speed in Nordic Holstein cattle. A total of 4,921 bulls genotyped with the BovineSNP50 BeadChip array were imputed to high-density genotypes (Illumina BovineHD BeadChip, Illumina, San Diego, CA) and, subsequently, to whole-genome sequence variants. An association analysis was carried out using a linear mixed model. Phenotypes used in the association analyses were deregressed breeding values. Multitrait meta-analysis was carried out for these 2 traits. We identified 10 and 8 chromosomes harboring markers that were significantly associated with udder index and milking speed, respectively. Strongest association signals were observed on chromosome 20 for udder index and chromosome 19 for milking speed. Multitrait meta-analysis identified 13 chromosomes harboring associated markers for the combination of udder index and milking speed. The associated region on chromosome 20 overlapped with earlier reported quantitative trait loci for similar traits in other cattle populations. Moreover, this region was located close to the FYB gene, which is involved in platelet activation and controls IL-2 expression; FYB is a strong candidate gene for udder health and worthy of further investigation.

Analysis of two susceptibility SNPs in HLA region and evidence of interaction between rs6457617 in HLA-DQB1 and HLA-DRB1*04 locus on Tunisian rheumatoid arthritis.

Previous genomewide association studies (GWAS) and meta-analyses have enumerated several genes/loci in major histocompatibility complex region, which are consistently associated with rheumatoid arthritis (RA) in different ethnic populations. Given the genetic heterogeneity of the disease, it is necessary to replicate these susceptibility loci in other populations. In this case, we investigate the analysis of two SNPs, rs13192471 and rs6457617, from the human leukocyte antigen (HLA) region with the risk of RA in Tunisian population. These SNPs were previously identified to have a strong RA association signal in several GWAS studies. A case-control sample composed of 142 RA patients and 123 healthy controls was analysed. Genotyping of rs13192471 and rs6457617 was carried out using real-time PCR methods by TaqMan allelic discrimination assay. A trend of significant association was found in rs6457617 TT genotype with susceptibility to RA (P = 0.04, pc = 0.08, OR = 1.73). Moreover, using multivariable analysis, the combination of rs6457617*TT-HLA-DRB1*04+ increased risk of RA (OR = 2.38), which suggest a gene-gene interaction event between rs6457617 located within the HLA-DQB1 and HLA-DRB1. Additionally, haplotypic analysis highlighted a significant association of rs6457617*T-HLA-DRB1*04+ haplotype with susceptibility to RA (P = 0.018, pc = 0.036, OR = 1.72). An evidence of association was shown subsequently in antiCCP+ subgroup with rs6457617 both in T allele and TT genotype (P = 0.01, pc = 0.03, OR = 1.66 and P = 0.008, pc = 0.024, OR = 1.28, respectively). However, no association was shown for rs13192471 polymorphism with susceptibility and severity to RA. This study suggests the involvement of rs6457617 locus as risk variant for susceptibility/severity to RA in Tunisian population. Secondly, it highlights the gene-gene interaction between HLA-DQB1 and HLA-DRB1.

Genetic association analysis of microRNA137 and its target complex 1 with schizophrenia in Han Chinese

Recent genome-wide association studies (GWAS) have identified a strong association signal of microRNA137 host gene (MIR137) with schizophrenia. MIR137 dysfunction results in downregulation of presynaptic target gene complexin 1 (CPLX1) and impairs synaptic plasticity in the hippocampus. In this study, we aimed to investigate whether the variants of MIR137 and CPLX1 confer susceptibility to schizophrenia in Han Chinese. This study employed 736 patients with schizophrenia patients and 751 well-matched healthy subjects for genetic analysis, and genotyped 12 SNPs within MIR137 and CPLX1. SZDB database was used to performed brain eQTL analysis. There were no significant differences of CPLX1 expression in hippocampus, prefrontal cortex or stratum between the schizophrenia patients and control subjects. No significant differences were observed in allele and genotype frequencies in studied SNPs between the case and control groups. Gene interaction analysis showed that MIR137 SNP rs1625579 did not affect schizophrenia susceptibility in interaction with the CPLX1 polymorphic variants. Our findings do not support MIR137 and CPLX1 conferring susceptibility to schizophrenia in Han Chinese.

The rs2292239 polymorphism in ERBB3 gene is associated with risk for type 1 diabetes mellitus in a Brazilian population

The Erb-b2 receptor tyrosine kinase 3 (ERBB3) belongs to a family of epidermal growth factor receptors of protein tyrosine kinases, and regulates cell survival, differentiation and proliferation in several cell types. Previous studies have suggested that ERBB3 contributes to T1DM pathogenesis by modulating antigen presenting cell function, autoimmunity and cytokine-induced beta-cell apoptosis. Accordingly, some genome-wide association studies identified ERBB3 gene as a susceptibility locus for T1DM, with the strongest association signal being observed for the rs2292239 single nucleotide polymorphism (SNP) in intron 7 of the gene. Therefore, the aim of the present study was to replicate the association of the ERBB3 rs2292239 SNP with T1DM in a Brazilian population. We analyzed 421 T1DM patients (cases) and 510 nondiabetic subjects (controls). All subjects were self-declared as white. The ERBB3 rs2292239 (A/C) SNP was genotyped by real-time PCR using TaqMan MGB probes. Genotype (P=0.001) and allele (P=0.002) frequencies of the ERBB3 rs2292239 SNP were differently distributed between T1DM patients and nondiabetic controls. Moreover, the A allele was significantly associated with risk for T1DM when considering recessive (OR=1.58, 95% CI 1.11–2.27; P=0.015), additive (OR=1.78, 95% CI 1.21–2.62; P=0.004), and dominant (OR=1.39, 95% CI 1.07–1.81; P=0.016) models of inheritance. However, after adjustment for presence of high-risk HLA DR/DQ genotypes, the rs2292239 SNP remained independently associated with T1DM only for the additive model (OR=1.62, 95% CI 1.02–2.59; P=0.043). Our results suggest that the A/A genotype of the ERBB3 rs2292239 SNP is associated with risk for T1DM in a white Brazilian population.

Genetic Analysis of Mitochondrial Ribosomal Proteins and Cognitive Aging in Postmenopausal Women.

Genes encoding mitochondrial ribosomal proteins (MRPs) have been linked to aging and longevity in model organisms (i.e., mice, Caenorhabditis elegans). Here we evaluated if the MRPs have conserved effects on aging traits in humans. We utilized data from 4,504 participants of the Women's Health Initiative Memory Study (WHIMS) who had both longitudinal cognitive data and genetic data. Two aging phenotypes were considered: (1) gross lifespan (time to all-cause mortality), and (2) cognitive aging (longitudinal rate of change in modified mini-mental state scores). We tested genetic association with variants in 78 members of the MRP gene family. Genetic association tests were done at the single nucleotide polymorphism (SNP) level, and at gene-set level using two distinct procedures (GATES and MAGMA). We included SNPs in APOE and adjusted the tests for the APOE-ε4 allele, a known risk factor for dementia. The strongest association signal is for the known cognitive aging SNP, rs429358, in APOE (p-value = 5 × 10−28 for cognitive aging; p-value = 0.03 for survival). We found no significant association between the MRPs and survival time. For cognitive aging, we detected SNP level association for rs189661478 in MRPL23 (p-value < 9 × 10−6). Furthermore, the gene-set analysis showed modest but significant association between the MRP family and cognitive aging. In conclusion, our results indicate a potential pathway-level association between the MRPs and cognitive aging that is independent of the APOE locus. We however did not detect association between the MRPs and lifespan.

Association of Common Variants in TGFA with Increased Risk of Knee Osteoarthritis Susceptibility.

Osteoarthritis (OA) is a complex degenerative joint disorder, which has contributions from both environmental and genetic factors. Several recent publications have established the connection between hip OA susceptibility and genetic markers within the TGFA gene, however, the relationship of these markers with knee OA has not been elucidated. Therefore, the present study was designed to investigate the potential linkage between common variants of the TGFA gene with knee OA in a large sample of Han Chinese individuals. We conducted a case-control study, including 338 knee OA patients and 985 unrelated healthy controls using both single nucleotide polymorphism (SNP) markers and haplotype-based analyses to examine the genotypic and allelic distribution of 19 tagging SNPs. We identified a significant association between the SNP rs2862851 and disease status of knee OA (p = 0.000314, OR = 1.40). Allelic analyses showed that the T allele of this SNP significantly elevated the risks of OA. This result was replicated in genotypic association analyses. In addition, haplotype-based analyses have also identified a strong association signal between one haplotype block, including rs2862851, and the disease status of knee OA (p < 0.00001). Our findings suggest that the rs2862851 allele of the TGFA gene may significantly contribute to the susceptibility to knee OA in the Han Chinese population.

Rapid Communication: High-resolution quantitative trait loci analysis identifies LTBP2 encoding latent transforming growth factor beta binding protein 2 associated with thoracic vertebrae number in a large F2 intercross between Landrace and Korean native pigs.

Number of vertebrae is associated with body size and meat productivity in pigs. The aim of this study was to identify QTL and associated positional candidate genes affecting the number of thoracic vertebrae (THO). A genomewide association study was conducted in a large resource population derived from an F intercross between Landrace and Korean native pigs using the Porcine SNP 60K BeadChip and the genomewide complex trait analysis (GCTA) program based on a linear mixed-effects model. A total of 38,385 SNP markers from 1,105 F progeny were analyzed for the THO trait after filtering for quality control. A total of 90 genomewide significant SNP markers ( < 1.30 × 10) on SSC 7 covering a 20-Mb region were identified for THO in this study. Several previous studies also mapped QTL for vertebral numbers in this region. The strongest association signals were detected at ASGA0035500 (-value = 4.46 × 10; 103,574,383 bp) and DIAS0000795 (-value = 4.46 × 10; 103,594,753 bp). The QTL region on SSC 7 for THO encompasses and , which are previously described candidate genes for vertebral number variation. To refine the QTL region, a haplotype-based linkage and linkage disequilibrium (LALD) analysis using the DualPHASE program was applied because subsequent conditional association and haplotype block analyses could not resolve the region that contains the 2 loci. The LALD analysis refined the critical region to a 533.9-kb region including ; was located outside the critical region. The gene encoding latent transforming growth factor beta binding protein 2 is involved in bone metabolisms. Based on these data, we propose as a positional candidate gene for THO in pigs. After further functional studies and verification of the association in other independent populations, these results could be useful for optimizing breeding programs that improve THO and other economically important traits in pigs.

Epigenome-wide Association of DNA Methylation in Whole Blood With Bone Mineral Density.

ABSTRACTGenetic and environmental determinants of skeletal phenotypes such as bone mineral density (BMD) may converge through the epigenome, providing a tool to better understand osteoporosis pathophysiology. Because the epigenetics of BMD have been largely unexplored in humans, we performed an epigenome‐wide association study (EWAS) of BMD. We undertook a large‐scale BMD EWAS using the Infinium HumanMethylation450 array to measure site‐specific DNA methylation in up to 5515 European‐descent individuals (NDiscovery = 4614, NValidation = 901). We associated methylation at multiple cytosine‐phosphate‐guanine (CpG) sites with dual‐energy X‐ray absorptiometry (DXA)‐derived femoral neck and lumbar spine BMD. We performed sex‐combined and stratified analyses, controlling for age, weight, smoking status, estimated white blood cell proportions, and random effects for relatedness and batch effects. A 5% false‐discovery rate was used to identify CpGs associated with BMD. We identified one CpG site, cg23196985, significantly associated with femoral neck BMD in 3232 females (p = 7.9 × 10−11) and 4614 females and males (p = 3.0 × 10−8). cg23196985 was not associated with femoral neck BMD in an additional sample of 474 females (p = 0.64) and 901 males and females (p = 0.60). Lack of strong consistent association signal indicates that among the tested probes, no large‐effect epigenetic changes in whole blood associated with BMD, suggesting future epigenomic studies of musculoskeletal traits measure DNA methylation in a different tissue with extended genome coverage. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Enhancing genomic prediction with genome-wide association studies in multiparental maize populations.

Genome-wide association mapping using dense marker sets has identified some nucleotide variants affecting complex traits that have been validated with fine-mapping and functional analysis. However, many sequence variants associated with complex traits in maize have small effects and low repeatability. In contrast to genome-wide association study (GWAS), genomic prediction (GP) is typically based on models incorporating information from all available markers, rather than modeling effects of individual loci. We considered methods to integrate results of GWASs into GP models in the context of multiple interconnected families. We compared association tests based on a biallelic additive model constraining the effect of a single-nucleotide polymorphism (SNP) to be equal across all families in which it segregates to a model in which the effect of a SNP can vary across families. Association SNPs were then included as fixed effects into a GP model that also included the random effects of the whole genome background. Simulation studies revealed that the effectiveness of this joint approach depends on the extent of polygenicity of the traits. Congruent with this finding, cross-validation studies indicated that GP including the fixed effects of the most significantly associated SNPs along with the polygenic background was more accurate than the polygenic background model alone for moderately complex but not highly polygenic traits measured in the maize nested association mapping population. Individual SNPs with strong and robust association signals can effectively improve GP. Our approach provides a new integrative modeling approach for both reliable gene discovery and robust GP.

SCOPA and META-SCOPA: software for the analysis and aggregation of genome-wide association studies of multiple correlated phenotypes

BackgroundGenome-wide association studies (GWAS) of single nucleotide polymorphisms (SNPs) have been successful in identifying loci contributing genetic effects to a wide range of complex human diseases and quantitative traits. The traditional approach to GWAS analysis is to consider each phenotype separately, despite the fact that many diseases and quantitative traits are correlated with each other, and often measured in the same sample of individuals. Multivariate analyses of correlated phenotypes have been demonstrated, by simulation, to increase power to detect association with SNPs, and thus may enable improved detection of novel loci contributing to diseases and quantitative traits.ResultsWe have developed the SCOPA software to enable GWAS analysis of multiple correlated phenotypes. The software implements “reverse regression” methodology, which treats the genotype of an individual at a SNP as the outcome and the phenotypes as predictors in a general linear model. SCOPA can be applied to quantitative traits and categorical phenotypes, and can accommodate imputed genotypes under a dosage model. The accompanying META-SCOPA software enables meta-analysis of association summary statistics from SCOPA across GWAS. Application of SCOPA to two GWAS of high-and low-density lipoprotein cholesterol, triglycerides and body mass index, and subsequent meta-analysis with META-SCOPA, highlighted stronger association signals than univariate phenotype analysis at established lipid and obesity loci. The META-SCOPA meta-analysis also revealed a novel signal of association at genome-wide significance for triglycerides mapping to GPC5 (lead SNP rs71427535, p = 1.1x10−8), which has not been reported in previous large-scale GWAS of lipid traits.ConclusionsThe SCOPA and META-SCOPA software enable discovery and dissection of multiple phenotype association signals through implementation of a powerful reverse regression approach.

A genome-wide association study of essential hypertension in an Australian population using a DNA pooling approach.

Despite the success of genome-wide association studies (GWAS) in detecting genetic loci involved in complex traits, few susceptibility genes have been detected for essential hypertension (EH). We aimed to use pooled DNA GWAS approach to identify and validate novel genomic loci underlying EH susceptibility in an Australian case-control population. Blood samples and questionnaires detailing medical history, blood pressure, and prescribed medications were collected for 409 hypertensives and 409 age-, sex- and ethnicity-matched normotensive controls. Case and control DNA were pooled in quadruplicate and hybridized to Illumina 1M-Duo arrays. Allele frequencies agreed with those reported in reference data and known EH association signals were represented in the top-ranked SNPs more frequently than expected by chance. Validation showed that pooled DNA GWAS gave reliable estimates of case and control allele frequencies. Although no markers reached Bonferroni-corrected genome-wide significance levels (5.0×10-8), the top marker rs34870220 near ASGR1 approached significance (p=4.32×10-7), as did several candidate loci (p<1×10-6) on chromosomes 2, 4, 6, 9, 12, and 17. Four markers (located in or near genes NHSL1, NKFB1, GLI2, and LRRC10) from the top ten ranked SNPs were individually genotyped in pool samples and were tested for association between cases and controls using the χ 2 test. Of these, rs1599961 (NFKB1) and rs12711538 (GLI2) showed significant difference between cases and controls (p<0.01). Additionally, four top-ranking markers within NFKB1 were found to be in LD, suggesting a single strong association signal for this gene.