A powerful test of independent assortment that determines genome-wide significance quickly and accurately

BackgroundGenetic and smoking contribute to chronic obstructive pulmonary disease (COPD), but whether a combined polygenic risk score (PRS) is associated with incident COPD and whether it has a synergistic effect on the smoking remains unclear. We aimed to investigate the association of PRS with COPD and explore whether smoking behaviors could modify such association.MethodsMultivariable Cox proportional models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association of the PRS and smoking with COPD.ResultsThe study included 439 255 participants (mean age 56.5; 53.9% female), with a median follow-up of 9.0 years. The PRSlasso containing 2.5 million variants showed better discrimination and a stronger association for incident COPD than the PRS279 containing 279 genome-wide significance variants. Compared with the low genetic risk, the HRs of the medium and high genetic risk were 1.39 (95% CI, 1.31–1.48) and 2.40 (95% CI, 2.24–2.56), respectively. The HR of high genetic risk and current smoking was 11.62 (95% CI, 10.31–13.10) times of low genetic risk and never smoking. There were significant interactions between the PRSlasso and smoking status for incident COPD (p for interaction<0.001). From low genetic risk to high genetic risk, the HRs of current smoking increased from 4.32 (95% CI, 3.69–5.06) to 6.89 (95% CI, 6.21–7.64), and the population-attributable risks of smoking increased from 42.7% to 61.1%.ConclusionPRS constructed from millions of variants below genome-wide significance showed significant associations with incident COPD. Participants with a high genetic risk may be more susceptible to developing COPD when exposed to smoking.

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Abstract MP82: The Effect of Nicotinic Acetylcholine Receptor Genes CHRNA3/5 on Thoracic Aortic Calcium is Mediated by Smoking

Circulation ◽

10.1161/circ.133.suppl_1.mp82 ◽

2016 ◽

Vol 133 (suppl_1) ◽

Author(s):

Sharon M Lutz ◽

Michael Cho ◽

Greg Kinney ◽

Kendra Young ◽

Katherine Pratte ◽

...

Keyword(s):

Risk Factors ◽

Genetic Risk ◽

Rare Variants ◽

Subclinical Atherosclerosis ◽

Significant Snps ◽

Smoking History ◽

Nicotinic Acetylcholine ◽

Genome Wide ◽

Significant Mediator ◽

Genome Wide Significance

Introduction: Coronary artery calcium (CAC) and thoracic aortic calcium (TAC), markers of subclinical atherosclerosis, have been shown to strongly correlate with the amount of atheromatous plaque and subsequently predict future coronary disease events and mortality. CAC and TAC are complex heritable traits with both genetic and environmental risk factors such as cigarette smoking. We investigated the role of smoking, a key environmental risk factor, as a mediator of the genetic risk of subclinical atherosclerosis in the COPDGene study. Hypothesis: We hypothesized that smoking will mediate a portion of the genome-wide significant SNPs with subclinical atherosclerosis as measured by TAC and CAC. Methods: We performed genome wide genotyping of common and rare variants in COPDGene, a study of 10,192 current and former smokers with at least 10 pack-years of smoking history. CAC and TAC were measured using high dose, inspiration chest CT scans, following an established protocol in 8,739 individuals (6,150 non-Hispanic Whites and 2,589 African Americans). Mediation analysis, using the significant SNPs from the GWA of common and rare variants, was performed using R software adjusting for genetic ancestry using principal components as well as recognized risk factors (age, gender, BMI, diabetes, high blood pressure, steroid use, high cholesterol, and presence of a coronary stent). We used the log transformation of CAC plus 1 and the log transformation of TAC plus 1 as the quantitative phenotypes. Results: There were 3 SNPs on chromosome 15q25 [CHRNA5/3] achieving genome-wide significance with TAC in non-Hispanic Whites, with the most significant result being rs951266 (p= 3.074e-8). We previously replicated 9 SNPs on chromosome 9 [CDKN2B-AS1] reaching genome-wide significance with CAC in non-Hispanic Whites. In African Americans, no genome-wide significant associations were identified. Given these findings, we tested for mediation of these genetic signals by pack-years of smoking among non-Hispanic Whites in the COPDGene study. Pack-years of smoking history was a significant mediator of CHRNA5/3 [rs951266] on TAC (p <0.001, 13% indirect effect), while smoking was not a significant mediator of CDKN2B-AS13 on CAC (p =0.58). Conclusions: The nicotinic acetylcholine receptor genes on chromosome 15 (CHRNA5/3) were significantly associated with thoracic aortic calcium in this cohort of heavy smokers. Cigarette smoking mediates this genetic risk for subclinical atherosclerosis and may offer an avenue for intervening on the genetic susceptibility to coronary artery disease.

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Abstract 46: Whole Genome Sequence Analysis Of Blood Pressure Phenotypes In The Trans-omics For Precision Medicine And Centers For Common Disease Genomics Programs

Circulation ◽

10.1161/circ.141.suppl_1.46 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Cited By ~ 2

Author(s):

Tanika N Kelly ◽

Xiao Sun ◽

Jennifer A Brody ◽

Sarah A Gagliano ◽

Karen Y He ◽

...

Keyword(s):

Blood Pressure ◽

Precision Medicine ◽

Rare Variants ◽

Minor Allele ◽

Common Disease ◽

Whole Genome ◽

Genome Wide ◽

Novel Variants ◽

Discovery Stage ◽

Genome Wide Significance

Background: Although genome-wide association studies (GWAS) have made important strides in localizing genomic regions associated with blood pressure (BP) phenotypes, the causal mechanisms underlying the vast majority of identified signals remain to be elucidated. Whole genome sequencing (WGS) provides an opportunity for novel genomic discoveries and high-resolution refinement of identified GWAS signals. Methods: This multi-stage genomic study of BP was conducted in an ancestrally diverse sample of up to 735,905 participants from 20 cohorts. In the discovery stage WGS study, variants with minor allele counts >10 were tested for association with systolic BP (SBP), diastolic BP (DBP), and hypertension (HTN) among 50,755 participants from the Trans-Omics for Precision Medicine and Centers for Common Disease Genomics programs using the Analysis Commons cloud based platform. Variants achieving suggestive genome-wide significance (P<1х10 -6 ) were tested for replication among UK Biobank (N=383,145) and Million Veterans Program (N=318,891) participants with GWAS data imputed to the TOPMed and 1000 Genomes reference panels, respectively. Results: Discovery stage analyses identified 63 novel loci suggestively associated with BP. As expected, most of these variants (81%) had minor allele frequencies (MAFs)<1%. Although none achieved genome-wide significance (P<5х10 -8 ) in joint analyses of discovery and replication stages, two rare variants had consistent effect directions and achieved nominal significance in replication analyses, including one for DBP at CHL1 (rs932205533; MAF=1.2х10 -4 ; joint β=18.0; joint P=7.4х10 -8 ) and one for SBP at MACROD2 (rs752530366; MAF=8.6х10 -4 ; joint β=-5.1; joint P=3.8х10 -6 ). A total of 44 novel variants from previously reported loci (r 2 <0.1 with previously reported variants) were also identified in the discovery stage analyses, including 31 rare variants with large effect sizes (70%). Nine common variants from these loci achieved genome-wide significance in joint analyses. Variants for SBP included ones at NPPB (rs12406089; MAF=0.34; joint β=-0.58; joint P=2.7х10 -79 ), AC137675.1 (rs2643826; MAF=0.56; joint β=0.56; joint P=1.5х10 -45 ), NEIL2 (rs804264; MAF=0.35; joint β=0.28; joint P=4.7х10 -20 ), CACNB2 (rs11014204; MAF=0.21; joint β=-0.53; joint P=6.8х10 -57 ), OVOL1 (rs557675; MAF=0.43; joint β=-0.25; joint P=1.9х10 -17 ), RP11-654D12.2 (rs8014582; MAF=0.05; joint β=-0.52; joint P=6.7х10 -13 ), and ATXN2 (rs35350651; MAF=0.67; joint β=-0.39; joint P=3.4х10 -38 ). Novel variants for DBP at INSR (rs36150639; MAF=0.45; joint β=-0.29; joint P=2.5х10 -27 ) and HTN at TBX3 (rs2891546; MAF=0.17; joint OR=0.95; joint P=3.1х10 -14 ) were also identified. Conclusion: WGS studies in large multi-ancestry samples can identify novel signals at previously reported GWAS loci, helping to localize causal genes and variants for BP.

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GWAS contribution to atrial fibrillation and atrial fibrillation-related stroke: pathophysiological implications

Pharmacogenomics ◽

10.2217/pgs-2019-0054 ◽

2019 ◽

Vol 20 (10) ◽

pp. 765-780 ◽

Cited By ~ 1

Author(s):

Diana Cruz ◽

Ricardo Pinto ◽

Margarida Freitas-Silva ◽

José Pedro Nunes ◽

Rui Medeiros

Keyword(s):

Atrial Fibrillation ◽

Genetic Variants ◽

Complex Traits ◽

Association Studies ◽

Cardioembolic Stroke ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Genetic Determinants ◽

Genome Wide ◽

Genome Wide Significance

Atrial fibrillation (AF) and stroke are included in a group of complex traits that have been approached regarding of their study by susceptibility genetic determinants. Since 2007, several genome-wide association studies (GWAS) aiming to identify genetic variants modulating AF risk have been conducted. Thus, 11 GWAS have identified 26 SNPs (p < 5 × 10-2), of which 19 reached genome-wide significance (p < 5 × 10-8). From those variants, seven were also associated with cardioembolic stroke and three reached genome-wide significance in stroke GWAS. These associations may shed a light on putative shared etiologic mechanisms between AF and cardioembolic stroke. Additionally, some of these identified variants have been incorporated in genetic risk scores in order to elucidate new approaches of stroke prediction, prevention and treatment.

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Genetic Study in a Large Cohort Supported Different Pathogenesis of Graves’ Disease and Hashimoto’s Hypothyroidism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa170 ◽

2020 ◽

Vol 105 (7) ◽

pp. e2600-e2608 ◽

Cited By ~ 2

Author(s):

Qian-Yue Zhang ◽

Wei Liu ◽

Lu Li ◽

Wen-Hua Du ◽

Chun-Lin Zuo ◽

...

Keyword(s):

Susceptibility Genes ◽

Graves Disease ◽

Susceptibility Loci ◽

Chinese Han ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Genome Wide ◽

Chinese Cohort ◽

First Time ◽

Genome Wide Significance

Abstract Context Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are the 2 main autoimmune thyroid diseases that have both similarities and differences. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these closely related diseases. Objects To identify the susceptibility genes for HT in the Chinese cohort and compare susceptibility genes between GD and HT. Design In the current study, 18 SNPs from 18 established GD risk loci were selected and then genotyped in 2682 patients with HT, 4980 patients with GD, and 3892 controls. The association analysis between HT and controls and heterogeneity analysis between HT and GD were performed on SPSS, with the logistic regression analysis adjusted for sex and age. Results We identified 11 susceptibility loci for HT in the Chinese Han population, with 4 loci, including the rs1265883 in SLAMF6 locus, rs1024161 in CTLA4, rs1521 in HLA-B, and rs5912838 in GPR174/ ITM2A at X chromosome, reaching genome-wide significance of 5 × 10–8. Five loci were reported to be associated with HT for the first time. We also identified 6 susceptibility loci with heterogeneity between GD and HT. Out of them, 4 loci were associated with GD but not with HT, including HLA-DPB1, CD40, TSHR, and TG; the association of HLA-B with GD was stronger than that with HT, but the association of SLAMF6 was reversed. Conclusion Our findings suggested that the pathogenesis of HT and GD was different.

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Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

Journal of the American Society of Nephrology ◽

10.1681/asn.2018101054 ◽

2019 ◽

Vol 30 (8) ◽

pp. 1375-1384 ◽

Cited By ~ 8

Author(s):

Stephanie Dufek ◽

Chris Cheshire ◽

Adam P. Levine ◽

Richard S. Trompeter ◽

Naomi Issler ◽

...

Keyword(s):

Immune Response ◽

Nephrotic Syndrome ◽

Genetic Identification ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Hla Association ◽

Genome Wide ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive ◽

Genome Wide Significance

BackgroundSteroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance.MethodsIn an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls.ResultsThe GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10−43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10−17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6.ConclusionsBecause CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

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Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance

Journal of Medical Genetics ◽

10.1136/jmedgenet-2014-102478 ◽

2014 ◽

Vol 51 (9) ◽

pp. 596-604 ◽

Cited By ~ 11

Author(s):

Yolande F M Ramos ◽

Sarah Metrustry ◽

Nigel Arden ◽

Anne C Bay-Jensen ◽

Marian Beekman ◽

...

Keyword(s):

Meta Analysis ◽

Genome Wide ◽

Genome Wide Significance

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Assessing genome-wide significance for the detection of differentially methylated regions

Statistical Applications in Genetics and Molecular Biology ◽

10.1515/sagmb-2017-0050 ◽

2018 ◽

Vol 17 (5) ◽

Cited By ~ 3

Author(s):

Christian M. Page ◽

Linda Vos ◽

Trine B. Rounge ◽

Hanne F. Harbo ◽

Bettina K. Andreassen

Keyword(s):

Multiple Testing ◽

Alternative Methods ◽

Scan Statistic ◽

Differentially Methylated Regions ◽

False Discovery ◽

Genome Wide ◽

Higher Power ◽

Health And Disease ◽

Rate Controlled ◽

Genome Wide Significance

AbstractDNA methylation plays an important role in human health and disease, and methods for the identification of differently methylated regions are of increasing interest. There is currently a lack of statistical methods which properly address multiple testing, i.e. control genome-wide significance for differentially methylated regions. We introduce a scan statistic (DMRScan), which overcomes these limitations. We benchmark DMRScan against two well established methods (bumphunter, DMRcate), using a simulation study based on real methylation data. An implementation of DMRScan is available from Bioconductor. Our method has higher power than alternative methods across different simulation scenarios, particularly for small effect sizes. DMRScan exhibits greater flexibility in statistical modeling and can be used with more complex designs than current methods. DMRScan is the first dynamic approach which properly addresses the multiple-testing challenges for the identification of differently methylated regions. DMRScan outperformed alternative methods in terms of power, while keeping the false discovery rate controlled.

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Genome wide association study of passive immunity and disease traits in beef-suckler and dairy calves on Irish farms

Scientific Reports ◽

10.1038/s41598-020-75870-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Dayle Johnston ◽

Robert Mukiibi ◽

Sinéad M. Waters ◽

Mark McGee ◽

Carla Surlis ◽

...

Keyword(s):

Genome Wide Association Study ◽

Association Studies ◽

Dairy Calves ◽

Genome Wide Association ◽

Passive Immunity ◽

Genome Wide Association Studies ◽

Serum Igg ◽

Genome Wide ◽

Beef Suckler ◽

Genome Wide Significance

Abstract Calves with lower concentrations of immunoglobulin G (IgG) in their blood, have a greater risk of developing diseases. There is a lack of knowledge on genetic markers known to be associated with immunological variability or disease resistance. Therefore, the objective of this study was to identify SNP markers associated with passive immunity measures (serum IgG, serum protein, albumin, globulin and total protein concentrations, total solids Brix percentage, zinc sulphate turbidity units) and disease (pneumonia, diarrhoea, crude illness) traits in Irish commercial beef-suckler and dairy calves through genome wide association studies (GWAS). Genotyping was performed on DNA samples from beef-suckler (n = 698) and dairy (n = 1178) calves, using the IDBv3 chip. Heritability of passive immunity associated traits (range 0.02–0.22) and the disease traits (range 0.03–0.20) were low-to-moderate. Twenty-five and fifteen SNPs approached genome wide significance (P < 5 × 10−5) for the passive immunity and the disease traits, respectively. One SNP “ARS-BFGL-BAC-27914” reached Bonferroni genome wide significance (P < 1.15 × 10−6) for an association with serum IgG concentration in beef calves. Further work will evaluate these SNPs in larger cattle populations and assess their contribution to genomic selection breeding strategies, aimed towards producing more disease resistant livestock.

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