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

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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Genome-wide association study reveals genetic risk factors for trigeminal neuralgia

10.1101/2021.02.08.21251349 ◽

2021 ◽

Author(s):

Andrew T. Hale ◽

Jing He ◽

Oluwatoyin Akinnusotu ◽

Rebecca L. Sale ◽

Janey Wang ◽

...

Keyword(s):

Risk Factors ◽

Trigeminal Neuralgia ◽

Genetic Risk ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Uk Biobank ◽

Genome Wide ◽

The Uk ◽

Genome Wide Significance

AbstractBackgroundWhile many clinical risk factors of trigeminal neuralgia (TN) have been identified, the genetic basis of TN is largely unknown. Here, we perform the first genome-wide association study (GWAS) for TN using three independent DNA biobanks – BioVU, the UK Biobank, and Finngen.ObjectiveTo elucidate the genetic basis of TN.MethodsUsing GWAS summary statistics generated from BioVU, the UK Biobank, and Finngen, we performed fixed-effect meta-analysis across 490,912 individuals (1,188 TN cases and 489,724 controls) to identify genetic risk factors for TN. Genome-wide significance was defined as p < 5.0×10−8.ResultsWe identify an intergenic locus on chromosome 1p22.2 flanked by ZNF326 and SNORD3G containing 5 SNPs (rs77449572, rs543311093, rs35117749, rs71666259, and rs116010656) reaching genome-wide significance (p < 5.0 x 10−8), where rs77449572 is the sentinel variant (p = 1.72 x 10−9). The SNP rs77449572 overlaps an enhancer element in cortex-derived neurospheres. In addition, rs71666259 and rs116010656 are located in enhancer elements in embryonic stem cells (HUES48), suggesting potential functional consequences of this locus. We also identify a second locus on chromosome 5q35.1 containing sentinel variant rs62376947 reaching genome-wide significance (p = 2.49 x 10−8).ConclusionsTo our knowledge, we perform the first GWAS of TN. Future studies should be aimed at understanding the extent to which genetic variation stratifies response to neuropathic pain medication and whether genetic information may be used to identify patients who are likely to benefit (or not) from surgical intervention.

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P6017 A high density genome-wide scan for genetic risk factors of insect bite hypersensitivity (IBH): A Horsegene Project Initiative

Journal of Animal Science ◽

10.2527/jas2016.94supplement4156a ◽

2016 ◽

Vol 94 (suppl_4) ◽

pp. 156-157

Author(s):

B. D. Velie ◽

M. Shrestha ◽

L. Francois ◽

A. Schurink ◽

A. Stinckens ◽

...

Keyword(s):

Risk Factors ◽

Genetic Risk ◽

Genetic Risk Factors ◽

High Density ◽

Genome Wide ◽

Insect Bite Hypersensitivity ◽

Genome Wide Scan

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Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk

Human Molecular Genetics ◽

10.1093/hmg/ddz145 ◽

2019 ◽

Vol 28 (20) ◽

pp. 3498-3513 ◽

Cited By ~ 15

Author(s):

Jennie G Pouget ◽

Buhm Han ◽

Yang Wu ◽

Emmanuel Mignot ◽

Hanna M Ollila ◽

...

Keyword(s):

Risk Factors ◽

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Phenotypic Correlation ◽

Biliary Cirrhosis ◽

Genome Wide ◽

Shared Genetic

Abstract Many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified five variants with potentially pleiotropic effects. While colocalization analyses were inconclusive, functional characterization of these variants provided the strongest evidence for a model in which genetic variation at rs1734907 modulates risk of schizophrenia and Crohn’s disease via altered methylation and expression of EPHB4—a gene whose protein product guides the migration of neuronal axons in the brain and the migration of lymphocytes towards infected cells in the immune system. Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using cross-trait LD score regression. Of the 11 immune diseases with available genome-wide summary statistics, we observed genetic correlation between six immune diseases and schizophrenia: inflammatory bowel disease (rg = 0.12 ± 0.03, P = 2.49 × 10−4), Crohn’s disease (rg = 0.097 ± 0.06, P = 3.27 × 10−3), ulcerative colitis (rg = 0.11 ± 0.04, P = 4.05 × 10–3), primary biliary cirrhosis (rg = 0.13 ± 0.05, P = 3.98 × 10−3), psoriasis (rg = 0.18 ± 0.07, P = 7.78 × 10–3) and systemic lupus erythematosus (rg = 0.13 ± 0.05, P = 3.76 × 10–3). With the exception of ulcerative colitis, the degree and direction of these genetic correlations were consistent with the expected phenotypic correlation based on epidemiological data. Our findings suggest shared genetic risk factors contribute to the epidemiological association of certain immune diseases and schizophrenia.

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Associations of genetic risk and smoking with incident chronic obstructive pulmonary disease

European Respiratory Journal ◽

10.1183/13993003.01320-2021 ◽

2021 ◽

pp. 2101320

Author(s):

Pei-Dong Zhang ◽

Xi-Ru Zhang ◽

Ao Zhang ◽

Zhi-Hao Li ◽

Dan Liu ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Genetic Risk ◽

Chronic Obstructive ◽

Polygenic Risk Score ◽

Obstructive Pulmonary Disease ◽

Current Smoking ◽

High Genetic Risk ◽

Genome Wide ◽

Genome Wide Significance

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 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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Critical Analysis of Genome-Wide Association Studies: Triple Negative Breast Cancer Quae Exempli Causa

International Journal of Molecular Sciences ◽

10.3390/ijms21165835 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5835

Author(s):

Maria-Ancuta Jurj ◽

Mihail Buse ◽

Alina-Andreea Zimta ◽

Angelo Paradiso ◽

Schuyler S. Korban ◽

...

Keyword(s):

Breast Cancer ◽

Risk Factors ◽

Genetic Risk ◽

Triple Negative ◽

Cancer Susceptibility ◽

Association Studies ◽

Breast Cancer Susceptibility ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Genome Wide

Genome-wide association studies (GWAS) are useful in assessing and analyzing either differences or variations in DNA sequences across the human genome to detect genetic risk factors of diseases prevalent within a target population under study. The ultimate goal of GWAS is to predict either disease risk or disease progression by identifying genetic risk factors. These risk factors will define the biological basis of disease susceptibility for the purposes of developing innovative, preventative, and therapeutic strategies. As single nucleotide polymorphisms (SNPs) are often used in GWAS, their relevance for triple negative breast cancer (TNBC) will be assessed in this review. Furthermore, as there are different levels and patterns of linkage disequilibrium (LD) present within different human subpopulations, a plausible strategy to evaluate known SNPs associated with incidence of breast cancer in ethnically different patient cohorts will be presented and discussed. Additionally, a description of GWAS for TNBC will be presented, involving various identified SNPs correlated with miRNA sites to determine their efficacies on either prognosis or progression of TNBC in patients. Although GWAS have identified multiple common breast cancer susceptibility variants that individually would result in minor risks, it is their combined effects that would likely result in major risks. Thus, one approach to quantify synergistic effects of such common variants is to utilize polygenic risk scores. Therefore, studies utilizing predictive risk scores (PRSs) based on known breast cancer susceptibility SNPs will be evaluated. Such PRSs are potentially useful in improving stratification for screening, particularly when combining family history, other risk factors, and risk prediction models. In conclusion, although interpretation of the results from GWAS remains a challenge, the use of SNPs associated with TNBC may elucidate and better contextualize these studies.

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Genetics of Keratoconus: Where Do We Stand?

Journal of Ophthalmology ◽

10.1155/2014/641708 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 27

Author(s):

Khaled K. Abu-Amero ◽

Abdulrahman M. Al-Muammar ◽

Altaf A. Kondkar

Keyword(s):

Risk Factors ◽

Candidate Gene ◽

Genetic Risk ◽

Current Knowledge ◽

Genetic Risk Factors ◽

Factors Associated ◽

Genetic Components ◽

Genome Wide ◽

Molecular Etiology

Keratoconus is a progressive thinning and anterior protrusion of the cornea that results in steepening and distortion of the cornea, altered refractive powers, and reduced vision. Keratoconus has a complex multifactorial etiology, with environmental, behavioral, and multiple genetic components contributing to the disease pathophysiology. Using genome-wide and candidate gene approaches several genomic loci and genes have been identified that highlight the complex molecular etiology of this disease. The review focuses on current knowledge of these genetic risk factors associated with keratoconus.

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