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

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.

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Abstract 14182: Genome Wide Association Study for High Sensitive Cardiac Troponin T Levels Identifies a Novel Gene in Europeans With Type 1 Diabetes

Circulation ◽

10.1161/circ.142.suppl_3.14182 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Tarunveer S Ahluwalia ◽

Frederik Persson ◽

Tine W Hansen ◽

Lise Tarnow ◽

Hans-Henrik Parving ◽

...

Keyword(s):

Type 1 Diabetes ◽

Association Study ◽

Gene Locus ◽

Genome Wide Association Study ◽

Troponin T ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide ◽

Increased Risk

Introduction: Adults with diabetes have a two to four folds increased risk of dying with heart disease compared to those without diabetes. Higher cardiac troponins, especially Troponin T (TnT) is a specific biomarker for cardiac injury also guiding management of chest pain and associated with increased risk of heart failure. Hypothesis: There is limited knowledge on genes regulating cardiac TnT levels. We conducted a genome wide association study (GWAS) for circulating cardiac TnT levels among individuals with type 1 diabetes (T1D). Methods: The study included 849 T1D individuals recruited from the outpatient clinic at Steno Diabetes Center Copenhagen, Denmark. Serum high sensitive TnT (hsTnT) levels were measured and log transformed for normalization after check for outliers (mean ± 4 SD). Genotyping on 538,448 single nucleotide variants (SNVs) was done using Illumina Human Core Exome Chip. After quality control filters: hardy weinberg equilibrium (p >10 -6 ), European ancestry, genotype call rates >95%, common variants were examined in 740 individuals with hs TnT data. We ran linear regression based additive genetic models adjusting for age, sex, diabetes duration and population sub structure using Plink and R statistical programs. P <5 x 10 -8 was genome wide significant (GWS) while 5 x 10 -8 < p < 1 x 10 -6 was considered suggestive. Results: Participants had a mean (SD) age of 43.7 (11.1) years, 57.4% were men, with diabetes duration of 28.0 (9.5) years, HbA1c 8.9 (1.3) % and 50.5% with diabetic nephropathy. Median (IQR) hsTnT levels were 64.7 (29.2-175.6) pg/ml. We identified a GWS missense common variant in the CISD3 gene locus on chromosome 17 (p=1.7 x 10 -8 ) for cardiac hsTnT levels. This gene codes CDGSH Iron Sulfur Domain 3 protein also called Mitochondrial Inner NEET Protein. Two suggestive loci were PTPRD (Protein Tyrosine Phosphatase Receptor Type D; p=4.9 x 10 -7 ) and DCC (DCC Netrin 1 Receptor; 6.6 x 10 -7 ) on chromosomes 9 and 18. PTPRD is a known GWS locus for hsTnT that we reconfirm among T1D individuals. Conclusions: We identify a novel gene locus for circulating cardiac hsTnT levels among T1D individuals of European ancestry. CISD3 is expressed in heart tissue regulating mitochondrial functions. Further validation is suggested.

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

Circulation ◽

10.1161/circ.142.suppl_3.15402 ◽

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.

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Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease

European Respiratory Journal ◽

10.1183/13993003.02269-2019 ◽

2021 ◽

pp. 1902269

Author(s):

Ho Namkoong ◽

Yosuke Omae ◽

Takanori Asakura ◽

Makoto Ishii ◽

Shoji Suzuki ◽

...

Keyword(s):

Association Study ◽

Mycobacterium Avium ◽

Odds Ratio ◽

Complex Disease ◽

Genome Wide Association Study ◽

Host Susceptibility ◽

Genome Wide Association ◽

European Ancestry ◽

Nucleotide Polymorphisms ◽

Genome Wide

RationaleNontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear.ObjectivesWe aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen.MethodsThis genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping.ResultsThe GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64E−13, odds ratio=0.54), which is in an intronic region of the calcineurin like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. This SNP was also significantly associated with the disease in patients of Korean (p=2.18E−12, odds ratio=0.54) and European (p=5.12E−03, odds ratio=0.63) ancestry.ConclusionsWe identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

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Genome-Wide Association Study in Patients with Pulmonary Mycobacterium Avium Complex Disease

SSRN Electronic Journal ◽

10.2139/ssrn.3251505 ◽

2018 ◽

Author(s):

Ho Namkoong ◽

Yosuke Omae ◽

Takanori Asakura ◽

Mitsunori Yoshida ◽

Shoji Suzuki ◽

...

Keyword(s):

Association Study ◽

Mycobacterium Avium ◽

Mycobacterium Avium Complex ◽

Complex Disease ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

Mycobacterium Avium Complex Disease

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Abstract 34: Genome-wide Association Study Identified New Susceptibility Loci To Coronary Artery Aneurysm-related In Kawasaki Disease

Circulation ◽

10.1161/circ.131.suppl_2.34 ◽

2015 ◽

Vol 131 (suppl_2) ◽

Author(s):

Kyu Yeun Kim ◽

Mo Kyung Jung ◽

Yoon-Sun Bae ◽

Woohyuk Ji ◽

Dongjik Shin ◽

...

Keyword(s):

Coronary Artery ◽

Kawasaki Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Coronary Artery Aneurysm ◽

Artery Aneurysm ◽

Genome Wide Association ◽

Korean Children ◽

Genome Wide ◽

Increased Risk

Kawasaki disease (KD) is an acute systemic vasculitis syndrome that predominantly affects children younger than 5 years of age, and may causes serious, sometimes life-threatening, cardiac sequela associated with coronary artery aneurysm (CAA). To identify genetic variants that confers a highly increased risk of coronary artery aneurysm-related in Kawasaki disease. In this study, we carried out genome-wide association study (GWAS) in a Korean children population including 102 CAA-related KD cases and 126 controls. Fifteen genetic loci were found to be significantly correlated with KD risk (P<1.0X10(-7)). Our case-control study revealed that rs4236089 C allele in chloride intracellular channel 5 (CLIC5) gene at 6p21.1 was significantly associated with KD patients with CAA (odds ratio (OR)=4.6, P=7.53X10(-7)). These findings suggest that the CLIC5 gene may play a crucial role in CAA development pathway of KD.

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Genome-wide Association Study of Pancreatic Fat: The Multiethnic Cohort Adiposity Phenotype Study

10.1101/2021.03.23.436581 ◽

2021 ◽

Author(s):

Samantha Streicher ◽

Unhee Lim ◽

S. Lani Park ◽

Yuqing Li ◽

Xin Sheng ◽

...

Keyword(s):

Type 2 Diabetes ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

European Ancestry ◽

American Population ◽

Pancreatic Fat ◽

Genome Wide ◽

Multiethnic Cohort

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10 -8 ) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10 -8 ) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also suggestively associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUT , and rs79967607 is in intron 1 of EPM2A . PLUT, a linkRNA, regulates transcription of an adjacent gene, PDX1 , that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

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Genome-wide association study identifies locus at chromosome 2q32.1 associated with syncope and collapse

Cardiovascular Research ◽

10.1093/cvr/cvz106 ◽

2019 ◽

Vol 116 (1) ◽

pp. 138-148 ◽

Cited By ~ 4

Author(s):

Katra Hadji-Turdeghal ◽

Laura Andreasen ◽

Christian M Hagen ◽

Gustav Ahlberg ◽

Jonas Ghouse ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

European Ancestry ◽

Psychiatric Research ◽

Carrier Status ◽

Genome Wide ◽

Common Genetic Variants ◽

A Genome ◽

Significant Locus

Abstract Aims Syncope is a common condition associated with frequent hospitalization or visits to the emergency department. Family aggregation and twin studies have shown that syncope has a heritable component. We investigated whether common genetic variants predispose to syncope and collapse. Methods and results We used genome-wide association data on syncope on 408 961 individuals with European ancestry from the UK Biobank study. In a replication study, we used the Integrative Psychiatric Research Consortium (iPSYCH) cohort (n = 86 189), to investigate the risk of incident syncope stratified by genotype carrier status. We report on a genome-wide significant locus located on chromosome 2q32.1 [odds ratio = 1.13, 95% confidence interval (CI) 1.10–1.17, P = 5.8 × 10−15], with lead single nucleotide polymorphism rs12465214 in proximity to the gene zinc finger protein 804a (ZNF804A). This association was also shown in the iPSYCH cohort, where homozygous carriers of the C allele conferred an increased hazard ratio (1.30, 95% CI 1.15–1.46, P = 1.68 × 10−5) of incident syncope. Quantitative polymerase chain reaction analysis showed ZNF804A to be expressed most abundantly in brain tissue. Conclusion We identified a genome-wide significant locus (rs12465214) associated with syncope and collapse. The association was replicated in an independent cohort. This is the first genome-wide association study to associate a locus with syncope and collapse.

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