Abstract 15402: A Multi-ethnic Genome Wide Association Study of Aortic Stenosis in the Million Veteran Program Identifies Several Novel Loci

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Aeron M Small ◽  
Gina Peloso ◽  
Jayashri Aragam ◽  
JASON LINEFSKY ◽  
Ashley Galloway ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Association Study ◽  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
High Morbidity ◽  
Genetic Loci ◽  
Genome Wide

Introduction: Valvular aortic stenosis (AS) is common with high morbidity and mortality in the absence of surgical intervention, but no current medical therapies are known to prevent or slow disease progression. Previous genetic studies have identified several genetic loci associated with prevalent AS, including LPA and PALMD , although most evidence is limited to populations of European ancestry. Methods: We performed a trans-ethnic genome-wide association study (GWAS) of prevalent AS in the Veterans Administration Million Veteran Program (MVP). Cases were identified by a combination of diagnostic billing and surgical codes and validated by association to the known LPA variant (rs10455872). GWAS was run separately for White, Black, and Hispanic individuals, controlling for age, sex, and six principal components, and combined using fixed effects meta-analysis. Results were limited to variants with a minor allele frequency greater than 1% in the trans-ancestry analysis. Lead independent genome wide significant loci were annotated by nearest gene. Results: 300,182 White, 80,744 Black, and 32,069 Hispanic participants were available for analysis. Of these, there were 12,385 (4.1%) White, 1,444 (1.8%) Black, and 611 (1.9%) Hispanic AS cases. Trans-ethnic analyses identified 10 independent genome wide significant (GWS, p≤5x10 -8 ) loci, replicating 6 known AS genetic loci ( ALPL, PALMD, TEX41, LPA, IL6, FADS1 ), and identifying 4 novel genetic loci ( CEP85L, CELSR2, NCK1, SLMAP ), of which 2 were present at nominal significance in Hispanic ( CELS2R ) or Black ( SLMAP ) individuals. Ethnicity-specific analyses additionally identified 9 novel GWS loci in White individuals, and 3 novel GWS loci in Hispanic individuals. Newly identified loci supported known biological pathways in AS including lipid/metabolic, inflammatory, and calcification, but also implicated new pathways such as those pertaining to QT interval ( SLC35F1 ) and the Brugada Syndrome ( SLMAP ). Conclusions: In this large trans-ethnic GWAS for AS we replicate previously identified genetic loci for AS, and identified several novel loci both in trans-ethnic and in ethnic-specific analyses. These loci implicate known and novel biological mechanisms for future prevention and treatment of AS.

scholarly journals Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci

2021 ◽  
Author(s):  
Tarunveer S Ahluwalia ◽  
Bram P Prins ◽  
Mohammadreza Abdollahi ◽  
Nicola J Armstrong ◽  
Stella Aslibekyan ◽  
...  
Keyword(s):  
Association Study ◽  
Interleukin 6 ◽  
Fixed Effects ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Heritability Estimate ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide ◽  
Increased Risk

Abstract Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

scholarly journals A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Astros Th. Skuladottir ◽  
Gyda Bjornsdottir ◽  
Muhammad Sulaman Nawaz ◽  
Hannes Petersen ◽  
Solvi Rognvaldsson ◽  
...  
Keyword(s):  
Association Study ◽  
Hearing Impairment ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Sequence Variants ◽  
Age Related ◽  
Genome Wide ◽  
A Genome

AbstractVertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (Ncases = 48,072, Ncontrols = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease.

scholarly journals Genome-wide association study of smoking trajectory and meta-analysis of smoking status in 842,000 individuals

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ke Xu ◽  
◽  
Boyang Li ◽  
Kathleen A. McGinnis ◽  
Rachel Vickers-Smith ◽  
...  
Keyword(s):  
Association Study ◽  
Complex Traits ◽  
Genome Wide Association Study ◽  
Hispanic Americans ◽  
Smoking Status ◽  
Meta Analysis ◽  
Smoking Behavior ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide

Abstract Here we report a large genome-wide association study (GWAS) for longitudinal smoking phenotypes in 286,118 individuals from the Million Veteran Program (MVP) where we identified 18 loci for smoking trajectory of current versus never in European Americans, one locus in African Americans, and one in Hispanic Americans. Functional annotations prioritized several dozen genes where significant loci co-localized with either expression quantitative trait loci or chromatin interactions. The smoking trajectories were genetically correlated with 209 complex traits, for 33 of which smoking was either a causal or a consequential factor. We also performed European-ancestry meta-analyses for smoking status in the MVP and GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN) (Ntotal = 842,717) and identified 99 loci for smoking initiation and 13 loci for smoking cessation. Overall, this large GWAS of longitudinal smoking phenotype in multiple populations, combined with a meta-GWAS for smoking status, adds new insights into the genetic vulnerability for smoking behavior.

scholarly journals A genome-wide association study identifies novel genetic loci associated with pulmonary embolism

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Krittanawong ◽  
B Narasimhan ◽  
J Hahn ◽  
Z Wang ◽  
K Johnson ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Lipid Metabolism ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genetic Loci ◽  
P Values ◽  
Genome Wide ◽  
A Genome

Abstract Background Pulmonary embolism (PE) is a life-threatening cardiovascular condition. Studies showed that PE patients were associated with disorders of lipid metabolism and had higher triglyceride and lower HDL-C levels compared with healthy. We conducted the genome-wide association study to identify novel loci contributing to PE. Methods We conducted a large-scale GWAS of PE in 5,466 PE cases and 461,219 controls of European ancestry from the UK Biobank (466,685 participants total). We used genome-wide summary statistics to test for enrichment of functional annotations using ENRICHR. Example pathways included in Enrichr for testing include membership of genes in pathway databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG), Wikipathway, PANTHER, BioCarta or NCI-Nature pathways. We analyzed the pathways using combined score and p-values which were well validated by comparing to several methods. For pathway analyses, we considered a nominal P-value threshold of 0.05. Results We identified genome-wide significant genetic associations in 63 independent genetic loci for PE (P<5.0x10–7). Our findings for top pathways highlight that lipid metabolism (LIPC, LCAT, NPC2), caffeine metabolism (NAT2), and sudden cardiac death (ABCG8) related genetic loci play an important role in PE alongside genes already associated with coagulation-thrombosis pathway (VWF, THPO, PTPN11, INPP5D, UROS, HMBS) (all p-values p-values <0.05). Conclusion Our findings uncovered unexpected novel factors of PE etiology, suggesting novel mechanistic concepts of PE pathophysiology. Funding Acknowledgement Type of funding source: None

scholarly journals Genome-wide Association Study of Periodontal Pocketing in Finnish Adults

2021 ◽  
Author(s):  
Paula Tegelberg ◽  
Jussi Miikkael Leppilahti ◽  
Atte Ylöstalo ◽  
Tellervo Tervonen ◽  
Johannes Kettunen ◽  
...  
Keyword(s):  
Association Study ◽  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Fixed Effects Model ◽  
Number Of Teeth ◽  
Genome Wide ◽  
A Genome ◽  
Additive Regression

Abstract Background: A genome‐wide association study is an analytical approach that investigates whether genetic variants across the whole genome contribute to disease progression. The aim of this study was to investigate genome-wide associations of periodontal condition measured as deepened periodontal pockets (≥ 4 mm) in Finnish adults. Methods: This study was based on the data of the national Health 2000 Survey (BRIF8901) in Finland and the Northern Finland Birth Cohort 1966 Study totalling 3,245 individuals. The genotype data were analyzed using the SNPTEST v.2.4.1. The number of teeth with deepened periodontal pockets (≥ 4 mm deep) was employed as a continuous response variable in additive regression analyses performed separately for the two studies and the results were combined in a meta-analysis applying a fixed effects model. Results: Genome-wide significant associations with the number of teeth with ≥ 4 mm deep pockets were not found at the p-level of < 5 × 10-8, while in total 27 loci reached the p-level of 5 x 10-6. Of the top hits, SNP rs4444613 in chromosome 20 showed the strongest association (p = 1.35 × 10–7).Conclusion: No statistically significant genome-wide associations with deepened periodontal pockets were found in this study.

scholarly journals Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels

2020 ◽  
Author(s):  
Mary Hoekstra ◽  
Hao Yu Chen ◽  
Jian Rong ◽  
Line Dufresne ◽  
Jie Yao ◽  
...  
Keyword(s):  
Association Study ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Linear Regression Models ◽  
Lipoprotein A ◽  
Genome Wide ◽  
A Genome

Objective: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the LPA locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance (P ≤5×10 -8 ). In addition to validating previous associations at LPA , APOE , and CETP , we identified a novel variant at the APOH locus, encoding β2GPI (beta2-glycoprotein I). The APOH variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047–0.081]; P =2.8×10 -13 ) and demonstrated a stronger effect after adjustment for variation at the LPA locus (β [95% CI] [ln nmol/L], 0.089 [0.076–0.10]; P =3.8×10 -42 ). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044–0.28]; P =0.0071). Conclusions: In a large-scale genome-wide association study of Lp(a) levels, we identified APOH as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.

scholarly journals Multi-Locus Genome-Wide Association Study and Genomic Selection of Kernel Moisture Content at the Harvest Stage in Maize

2021 ◽  
Vol 12 ◽  
Author(s):  
Guangfei Zhou ◽  
Qiuli Zhu ◽  
Yuxiang Mao ◽  
Guoqing Chen ◽  
Lin Xue ◽  
...  
Keyword(s):  
Moisture Content ◽  
Association Study ◽  
Genomic Selection ◽  
Candidate Genes ◽  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Minor Effect ◽  
Genetic Loci ◽  
Genome Wide

Kernel moisture content at the harvest stage (KMC) is an important trait that affects the mechanical harvesting of maize grain, and the identification of genetic loci for KMC is beneficial for maize molecular breeding. In this study, we performed a multi-locus genome-wide association study (ML-GWAS) to identify quantitative trait nucleotides (QTNs) for KMC using an association mapping panel of 251 maize inbred lines that were genotyped with an Affymetrix CGMB56K SNP Array and phenotypically evaluated in three environments. Ninety-eight QTNs for KMC were detected using six ML-GWAS models (mrMLM, FASTmrMLM, FASTmrEMMA, PLARmEB, PKWmEB, and ISIS EM-BLASSO). Eleven of these QTNs were considered to be stable, as they were detected by at least four ML-GWAS models under a uniformed environment or in at least two environments and BLUP using the same ML-GWAS model. With qKMC5.6 removed, the remaining 10 stable QTNs explained &lt;10% of the phenotypic variation, suggesting that KMC is mainly controlled by multiple minor-effect genetic loci. A total of 63 candidate genes were predicted from the 11 stable QTNs, and 10 candidate genes were highly expressed in the kernel at different time points after pollination. High prediction accuracy was achieved when the KMC-associated QTNs were included as fixed effects in genomic selection, and the best strategy was to integrate all KMC QTNs identified by all six ML-GWAS models. These results further our understanding of the genetic architecture of KMC and highlight the potential of genomic selection for KMC in maize breeding.

scholarly journals Genome-wide association study of periodontal pocketing in Finnish adults

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Paula Tegelberg ◽  
Jussi Miikkael Leppilahti ◽  
Atte Ylöstalo ◽  
Tellervo Tervonen ◽  
Johannes Kettunen ◽  
...  
Keyword(s):  
Association Study ◽  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Fixed Effects Model ◽  
Number Of Teeth ◽  
Genome Wide ◽  
A Genome ◽  
Additive Regression

Abstract Background A genome‐wide association study is an analytical approach that investigates whether genetic variants across the whole genome contribute to disease progression. The aim of this study was to investigate genome-wide associations of periodontal condition measured as deepened periodontal pockets (≥ 4 mm) in Finnish adults. Methods This study was based on the data of the national Health 2000 Survey (BRIF8901) in Finland and the Northern Finland Birth Cohort 1966 Study totalling 3,245 individuals. The genotype data were analyzed using the SNPTEST v.2.4.1. The number of teeth with deepened periodontal pockets (≥ 4 mm deep) was employed as a continuous response variable in additive regression analyses performed separately for the two studies and the results were combined in a meta-analysis applying a fixed effects model. Results Genome-wide significant associations with the number of teeth with ≥ 4 mm deep pockets were not found at the p-level of < 5 × 10−8, while in total 17 loci reached the p-level of 5 × 10−6. Of the top hits, SNP rs4444613 in chromosome 20 showed the strongest association (p = 1.35 × 10−7). Conclusion No statistically significant genome-wide associations with deepened periodontal pockets were found in this study.

scholarly journals Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes

2021 ◽  
Vol 7 (2) ◽  
pp. e557
Author(s):  
Isabel Alfradique-Dunham ◽  
Rami Al-Ouran ◽  
Rainer von Coelln ◽  
Cornelis Blauwendraat ◽  
Emily Hill ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Association Study ◽  
Essential Tremor ◽  
Genetic Risk ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Risk Variants ◽  
Genome Wide

ObjectiveTo discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms.MethodsIn 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.ResultsAmong 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = −0.04, 95% confidence interval = −0.07–0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6 × 10−7), which harbors an independent risk allele for essential tremor.ConclusionsMultiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.

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