MON-LB129 A Pilot Genome Wide Association Study (GWAS) on Primary Aldosteronism Patients in a Multi-Ethnic Malaysian Cohort

Abstract Studies on excised aldosterone-producing lesions have found somatic mutations in five genes (KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1) commonly causes the excess aldosterone production. Interestingly, Oriental cohorts had the highest frequency of KCNJ5 mutations whereas CACNA1D mutations were most common in Black African Caribbean patients, suggesting that genetic background affects the prevalence and distribution of aldosterone-driving somatic mutation. We therefore aimed to identify the common germline variants that associates with excess aldosterone production through performing a pilot genome wide association study (GWAS) on primary aldosteronism (PA) patients. GWAS was performed using the Human Infinium OmniExpressExome-8 v1.4 BeadChip containing 960,919 markers to compare gDNA of 154 PA patients with 78 healthy controls. Samples were checked for sex discordance, heterozygosity rate, missing rate and the degree of recent shared ancestry for each pair of individuals using the PLINK program and Genome Studio (Illumina). In total, 150 patients and 75 controls (112 males and 113 females) were included in the downstream analysis. 630,749 markers that passed quality control steps (missing call rate <95% and minor allele frequency in controls >1%) were used to perform association analysis using the Chi-square Test which was then subjected to multiple testing corrections (Bonferroni correction). As expected with a pilot sample size, no variants passed the suggestive significant threshold of Bonferroni corrected P-value < 5 x 10-6 (-log10 P = 5.3). However, 27 SNPs had the uncorrected P-value<0.0002, odds ratio >2, and differences of frequencies in cases compared to control >0.1 or <-0.2, of which 3 genes (SRGAP3, AUTS2, and RORA) associated with these SNPs were also highlighted in the UK Biobank database of 72 patients with primary aldosteronism (https://biobankengine.stanford. edu/coding/HC189). Of these, RORA has recently been found to be down-regulated in adrenals from PA patients and spontaneously hypertensive rat adrenals compared to control adrenalsa,b. RORA encodes for the protein retinoic acid receptor (RAR)-related orphan receptor alpha, a member of the NR1 subfamily of nuclear hormone receptors (NR1F1). Interestingly, adrenal is the second organ to skin with the highest expression of RORA and treatment of angiotensin II in the adrenocortical cell line H295R increases RORA expressionc,d. Taken together, this pilot GWAS highlights RORA as a potential nuclear hormone receptor that regulates aldosterone production. References aChu et al., Int J Clin Exp Pathol 2017;10(9):10009-10018. bTanaka et al., Hypertens Res 2019;42(2):165-173. cNogueira et al., Mol Cell Endocrinol 2009; 302(2): 230–236. dGTEx Analysis Release V7 (dbGaP Accession phs000424.v7.p2) Acknowledgements This research was supported by the Malaysian Ministry of Higher Education Grant (FRGS/1/2015/SKK08/UKM/02/3), The National University of Malaysia (UKM) University Grant (GUP-2016-083), and The UKM Medical Center Fundamental Grant (FF-2016-302).

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Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112,117)

10.1101/116707 ◽

2017 ◽

Cited By ~ 8

Author(s):

Toni-Kim Clarke ◽

Mark J. Adams ◽

Gail Davies ◽

David M. Howard ◽

Lynsey S. Hall ◽

...

Keyword(s):

Alcohol Consumption ◽

Association Study ◽

Genome Wide Association Study ◽

Hdl Cholesterol ◽

Genome Wide Association ◽

P Value ◽

Uk Biobank ◽

Genome Wide ◽

A Genome ◽

Genetic Overlap

AbstractAlcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well known genetic variants in alcohol metabolizing genes, e.g. ALDH2, ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112,117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 8 independent loci. These include SNPs in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and 2 loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, PXDN, CADM2 and TNFRSF11A. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (CRHR1, DRD2), and genes previously associated with alcohol consumption (AUTS2). GCTA-GREML analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (S.E.=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation between male and female alcohol consumption was 0.73 (S.E.=0.09, p-value = 1.37 x 10−16). Using LD score regression, genetic overlap was found between alcohol consumption and schizophrenia (rG=0.13, S.E=0.04), HDL cholesterol (rG=0.21, S.E=0.05), smoking (rG=0.49, S.E=0.06) and various anthropometric traits (e.g. Overweight, rG=-0.19, S.E.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies 4 novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.

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PARALLEL MULTI-PROPOSAL AND MULTI-CHAIN MCMC FOR CALCULATING P-VALUE OF GENOME-WIDE ASSOCIATION STUDY

Parallel Processing Letters ◽

10.1142/s0129626413500084 ◽

2013 ◽

Vol 23 (03) ◽

pp. 1350008 ◽

Cited By ~ 1

Author(s):

DI ZHAO ◽

SHENGHUA NI

Keyword(s):

Monte Carlo ◽

Association Study ◽

High Performance ◽

Genome Wide Association Study ◽

Convergence Condition ◽

Genome Wide Association ◽

P Value ◽

The Novel ◽

Genome Wide ◽

Multiple Chain

In this paper, by the novel idea of integrating multiple-proposal algorithm and multiple-chain algorithm by parallel computing, we develop a highly efficient sampler for approximating statistical distributions: parallel Multi-proposal and Multi-chain Markov Chain Monte Carlo (pMPMC3), and we illustrate the high performance of this sampler by calculating P-value (odds ratio significance) for Genome Wide Association Study (GWAS). Computational results show that, by setting the convergence condition as the standard deviation of P-value is less than 10−3, pMPMC3 with 4 proposals and 4 chains obtains a convergent P-value within 106 iterations, while the conventional method Monte Carlo simulation does not obtain convergent P-values even in 107 iterations. We also test pMPMC3 by changing the number of chains, the number of proposals and the size of the dataset on a cluster with maximum 600 processes, the algorithm scales well.

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A family-based genome-wide association study reveals an association of spondyloarthritis with MAPK14

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-209449 ◽

2016 ◽

Vol 76 (1) ◽

pp. 310-314 ◽

Cited By ~ 3

Author(s):

Félicie Costantino ◽

Alice Talpin ◽

Roula Said-Nahal ◽

Ariane Leboime ◽

Elena Zinovieva ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

P Value ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Gwas Study ◽

Genome Wide ◽

Multiplex Families ◽

Family Based

ObjectiveMore than 40 loci have been associated with ankylosing spondylitis (AS), but less is known about genetic associations in spondyloarthritis (SpA) as a whole. We conducted a family-based genome-wide association study (GWAS) to identify new non-major histocompatibility complex (MHC) genetic factors associated with SpA.Methods906 subjects from 156 French multiplex families, including 438 with SpA, were genotyped using Affymetrix 250K microarrays. Association was tested with Unphased. The best-associated non-MHC single nucleotide polymorphisms (SNPs) were then genotyped in two independent familial cohorts (including 215 French and 294 North American patients with SpA, respectively) to replicate associations.Results43 non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1×10−4). In the extension studies, association was replicated at a nominal p value of p<0.05 for 16 SNPs in the second cohort and for three SNPs in the third cohort. Combined analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=3.5×10−7). Such association appeared to be independent of HLA-B27.ConclusionsWe report here for the first time a family-based GWAS study on SpA and identified an associated polymorphism near MAPK14. Further analyses are needed to better understand the functional basis of this genetic association.

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A Genome-Wide Association Study for Melatonin Secretion

10.21203/rs.3.rs-687475/v1 ◽

2021 ◽

Author(s):

Pi-Hua Liu ◽

Gwo-Tsann Chuang ◽

Chia-Ni Hsiung ◽

Wei-Shun Yang ◽

Hsiao-Chia Ku ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

P Value ◽

Melatonin Level ◽

Nucleotide Polymorphisms ◽

Melatonin Secretion ◽

Genome Wide ◽

A Genome ◽

Wide Range

Abstract SummaryPurpose: Melatonin exerts a wide range of effects among various tissues and organs. However, there is currently no study to investigate the genetic determinants of melatonin secretion. Here, we conducted a genome-wide association study (GWAS) for melatonin secretion using morning urine 6-hydroxymelatonin sulfate-to-creatinine ratio (UMCR). Methods: We initially enrolled 5,000 participants from Taiwan Biobank in this study. After excluding individuals that did not have their urine collected in the morning and those who failed to pass quality control, association of single nucleotide polymorphisms with log-transformed UMCR adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for estimated glomerular filtration rate (eGFR). Results: A total of 2,504 participants underwent the genome-wide analysis. Six candidate loci associated with log UMCR (P value ranging from 7.54 x 10-7 to 4.65 x 10-6) encompassing GALNT15, ZFHX3, NKAIN2, MME and NBPF22P were identified. Similar results were yielded with further adjustment for eGFR. Interestingly, the identified genes are associated with central nervous system function and clinical condition such as Alzheimer's disease or sleep disorders.Conclusions: We conducted the first GWAS for melatonin secretion and identified six candidate genetic loci associated with melatonin level. Replication and functional studies are needed in the future.

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Genome-wide association study identifies 17 new loci influencing concentrations of circulating cytokines and growth factors

10.1101/045005 ◽

2016 ◽

Cited By ~ 2

Author(s):

AV Ahola-Olli ◽

P Würtz ◽

AS Havulinna ◽

K Aalto ◽

N Pitkänen ◽

...

Keyword(s):

Growth Factors ◽

Association Study ◽

Molecular Mechanisms ◽

Genome Wide Association Study ◽

Metabolic Diseases ◽

Genome Wide Association ◽

Cytokine Signaling ◽

P Value ◽

Genome Wide ◽

Circulating Cytokines

AbstractCirculating cytokines and growth factors are regulators of inflammation and have been implicated in autoimmune and metabolic diseases. In this genome-wide association study (GWAS) up to n=8,293 Finns we identified 27 loci with genome-wide association (P-value<1.2×10-9) for one or more cytokines, including 17 unidentified in previous GWASes. Fifteen of the associated SNPs had expression quantitative trait loci in whole blood. We provide strong genetic instruments to clarify the causal roles of cytokine signaling and upstream inflammation in immune-related and other chronic diseases. We further link known autoimmune disease variants including Crohn's disease, multiple sclerosis and ulcerative colitis with new inflammatory markers, which elucidate the molecular mechanisms underpinning these diseases and suggest potential drug targets.

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A Genome Wide Association Study Reveals Genetic Predisposition for Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma By Variation in the PREP1-Cbs Locus

Blood ◽

10.1182/blood.v124.21.2057.2057 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2057-2057

Author(s):

Florence Magrangeas ◽

Rowan Kuiper ◽

Hervé Avet-loiseau ◽

Wilfried Gouraud ◽

Catherine Guérin ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Association Study ◽

Genetic Predisposition ◽

Research Funding ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

P Value ◽

Discovery Cohort ◽

Genome Wide ◽

A Genome

Abstract Introduction: Bortezomib has become an important part of myeloma therapy, despite the occurrence of toxicities such as bortezomib induced peripheral neuropathy (BiPN). Since effective prophylactic treatment is lacking, onset of BiPN can only be remedied by dose reduction or stop of treatment. Here, using a genome-wide genotyping method, we investigated the potential genetic predisposition to BiPN in MM patients who received bortezomib-dexamethasone (VD) induction therapy prior to autologous stem-cell transplantation (ASCT). Methods: We performed a genome-wide association study using the Affymetrix SNP 6.0 platform. In total 469 cases from the IFM 2005-01, IFM2007-02 clinical trials or routine diagnostic were included as discovery cohort. Another 114 samples from the HOVON-65/GMMG-HD4 trial were used as validation. Patients with BiPN grade 2 or higher after initiation of bortezomib treatment were assigned as cases (n=155 in discovery, n=40 in validation) and the remaining patients that did not developed BiPN were considered controls (n=314 in discovery, n=74 in validation). Additional exclusion criteria were a minor allele frequency ≤ 5%, genotype frequency < 95% or Hardy Weinberg equilibrium p-value <1 x 10-5; 371,075 tagging SNPs were thus included for analysis. Association of SNPs to BiPN was tested using a Cochran-Armitage trend test. Six SNPs were found with parametric p-value < 1 x 10-5. These SNPs were validated using the validation cohort. Results: Of three loci identified by six SNPs in the discovery cohort, one previously unreported gene locus (rs2839629) remained associated to BiPN in the validation data set. This locus at 21q22.3 had odd ratios of 1.89 (p<1x10-6) and 2.02 (p = 0.02) in the discovery and validation cohorts, respectively. It is localized in the 3’ UTR of PBX/knotted 1 homeobox 1 (PKNOX1; alias PREP1), which encodes for a homeodomain transcription factor. Amongst others, PKNOX1 may modulate levels of chemokine monocyte chemoattractant protein-1 (MCP-1). MCP-1 is universally increased in different models of peripheral neuropathic pain and may be considered as a biomarker of chronic pain (Zhang and de Koninck, J. Neurochem. 97:772-783 (2006)). Haplotype analysis revealed a strong linkage disequilibrium (LD, r2 = 0.87) to the neighbouring gene CBS which encodes an endogenous H2S-producing enzyme. The CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models (Takahashi et al., Pain, 150, 183-191, 2010). Conclusions: Our data provides evidence for susceptibility to BiPN in MM by variation in the PREP1-CBS locus, and suggests a new potential target in neuro-protective strategies of treatment. Validation of this finding may allow for the identification of patients at increased risk of BiPN which may benefit alternative treatments such as carfilzomib and better clinical management of this toxicity. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Moreau:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A genome-wide association study in progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458512439118 ◽

2012 ◽

Vol 18 (10) ◽

pp. 1384-1394 ◽

Cited By ~ 40

Author(s):

Filippo Martinelli-Boneschi ◽

Federica Esposito ◽

Paola Brambilla ◽

Eva Lindström ◽

Giovanni Lavorgna ◽

...

Keyword(s):

Multiple Sclerosis ◽

Association Study ◽

Genome Wide Association Study ◽

Axonal Guidance ◽

Genome Wide Association ◽

P Value ◽

Suggestive Evidence ◽

Genome Wide ◽

A Genome ◽

Herv Element

Background: The role played by genetic factors in influencing the clinical course of multiple sclerosis (MS) is not yet well established. Objective: We aimed to identify genetic variants associated with progressive MS (PrMS). Methods: We conducted a genome-wide association study (GWAS) in 197 patients with PrMS and 234 controls of Italian origin. We tested the top 20 single nucleotide polymorphisms (SNPs) with suggestive evidence of association ( p-value<10−4) in two independent sets of primary progressive MS cases and controls. Results: We identified a risk-associated SNP in the HLA region in linkage disequilibrium (LD) with DRB1*1501 and DQB*0602 loci, with genome-wide significance (rs3129934T, pcombined=6.7×10-16, OR=2.34, 95% CI=1.90–2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343G, pcombined=2.4×10-5, OR=0.70, 95% CI=0.59–0.83) which maps within a human endogenous retroviral (HERV) element. The new locus did not have a ‘ cis’ effect on RNA expression in lymphoblastic cell lines, but pathway analyses of ‘ trans’ effects point to an expression regulation of genes involved in neurodegeneration, including glutamate metabolism ( p<0.01) and axonal guidance signalling ( p<0.02). Conclusions: We have confirmed the established association with the HLA region and, despite the low statistical power of the study, we found suggestive evidence for association with a novel locus on chromosome 7, with a putative regulatory role.

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Genome-wide association studies of LRRK2 modifiers of Parkinson's disease

10.1101/2020.12.14.20224378 ◽

2020 ◽

Author(s):

Dongbing Lai ◽

Babak Alipanahi ◽

Pierre Fontanillas ◽

Tae-Hwi Schwantes-An ◽

Jan Aasly ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Age At Onset ◽

Genome Wide Association ◽

P Value ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Genome Wide

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods: We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value=2.5E-08, beta=1.27, SE=0.23, risk allele: C) met genome-wide significance for the penetrance model. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value=1.1E-07; age-at-onset top variant: P-value=9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations.

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FAPI: Fast and accurate P-value Imputation for genome-wide association study

European Journal of Human Genetics ◽

10.1038/ejhg.2015.190 ◽

2015 ◽

Vol 24 (5) ◽

pp. 761-766 ◽

Cited By ~ 8

Author(s):

Johnny SH Kwan ◽

Miao-Xin Li ◽

Jia-En Deng ◽

Pak C Sham

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

P Value ◽

Genome Wide

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Non-Syndromic Cleft Lip with or without Cleft Palate: Genome-Wide Association Study in Europeans Identifies a Suggestive Risk Locus at 16p12.1 and Supports SH3PXD2A as a Clefting Susceptibility Gene

Genes ◽

10.3390/genes10121023 ◽

2019 ◽

Vol 10 (12) ◽

pp. 1023 ◽

Cited By ~ 3

Author(s):

Iris ALM van Rooij ◽

Kerstin U Ludwig ◽

Julia Welzenbach ◽

Nina Ishorst ◽

Michelle Thonissen ◽

...

Keyword(s):

Cleft Palate ◽

Association Study ◽

Cleft Lip ◽

Genome Wide Association Study ◽

Susceptibility Gene ◽

Small Sample ◽

Genome Wide Association ◽

P Value ◽

Genome Wide ◽

A Genome

Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 × 10−7). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.

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