Biases in GWAS – the dog that did not bark

Schooling, CM

doi:10.1101/709063

Cited by 9 publications

(8 citation statements)

References 26 publications

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“…Accordingly, gene-set-based analysis by Open Target Post GWAS highlighted the probable pleiotropic effects of detected loci, which are likely acting as a common genetic etiology for BP and cardiovascular diseases. Accordingly, the lethal cardiovascular diseases may affect allele frequency of effective variants with advancing age in our study due to survival reduction, so overlook the effect of functional variants in older groups as a competing risk [42,43].…”

Section: Discussionmentioning

confidence: 83%

Genome-Wide Association Study on Blood Pressure Traits in the Iranian Population Suggests ZBED9 as A New Locus for Hypertension.

Kolifarhood

Sabour

Akbarzadeh

et al. 2020

Preprint

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High blood pressure is the heritable risk factor for cardiovascular and kidney diseases. Genome-wide association studies(GWAS) on blood pressure traits increase our understanding of its underlying genetic basis. However, a large proportion of GWAS was conducted in Europeans, and some roadblocks deprive other populations to benefit from their results. Iranians population with a high degree of genomic specificity has not been represented in international databases to date, so to fill the gap, we explored the effects of 652,919 genomic variants on Systolic Blood Pressure(SBP), Diastolic Blood Pressure(DBP), and Hypertension(HTN) in 7,694 Iranian adults aged 18 and over from Tehran Cardiometabolic Genetic Study(TCGS). We identified consistent signals on ZBED9 associated with HTN in the genome-wide borderline threshold after adjusting for two different sets of environmental predictors(P value=2.21×10-7). Moreover, strong signals on ABHD17C and suggestive signals on FBN1 were detected for DBP and SBP, respectively, while these signals were not consistent in different GWA analysis. Our finding on ZBED9 was confirmed for all BP traits by linkage analysis in an independent sample. Although there is no strong evidence to support the function of ZBED9 in blood pressure regulation, it provides new insight into the pleiotropic effects of hypertension and other cardiovascular diseases.

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Section: Discussionmentioning

confidence: 83%

Genome-Wide Association Study on Blood Pressure Traits in the Iranian Population Suggests ZBED9 as A New Locus for Hypertension.

Kolifarhood

Sabour

Akbarzadeh

et al. 2020

Preprint

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“…We also acknowledge that GWAS of associations of genetic variants on chronic diseases can be prone to selection bias from surviving competing risk. Methods to assess genetic effects on chronic diseases are needed to account for competing risk before recruitment [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study

Khoei

Carreras‐Torres

Murphy

et al. 2021

Cells

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Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin’s lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin’s lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated (p < 5 × 10−8) with circulating total bilirubin, extracted from a genome-wide association study in the UK Biobank, were used as instrumental variables. One SNP (rs6431625) in the promoter region of the uridine-diphosphoglucuronate glucuronosyltransferase1A1 (UGT1A1) gene explained 16.9% and the remaining 114 SNPs (non-UGT1A1 SNPs) explained 3.1% of phenotypic variance in circulating bilirubin levels. A one-standarddeviation increment in circulating bilirubin (≈ 4.4 µmol/L), predicted by non-UGT1A1 SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin’s lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73–0.99, P 0.04 and OR 0.64, 95% CI 0.42–0.99, p 0.04, respectively), which was confirmed after removing potential pleiotropic SNPs. In contrast, a positive association was observed with the risk of breast cancer after removing potential pleiotropic SNPs (OR 1.12, 95% CI 1.04–1.20, p 0.002). There was little evidence for robust associations with the other seven cancers investigated. Genetically raised bilirubin levels were inversely associated with risk of squamous cell lung cancer as well as Hodgkin’s lymphoma and positively associated with risk of breast cancer. Further studies are required to investigate the utility of bilirubin as a low-cost clinical marker to improve risk prediction for certain cancers.

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“…As smoking and alcohol drinking are strongly associated with survival, we performed analyses stratified by median age at study of cases and controls (67 years) and examined whether MR estimates observed overall were consistent with those seen in younger participants in whom survival bias is unlikely as mortality rates are low in this group. [25][26][27] The consortium included prevalent and incident patients. If genetic variants have a stronger effect on survival in PD patients than controls, genetic associations may be biased.…”

Section: Statistical Analysesmentioning

confidence: 99%

Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson’s Disease

Domenighetti¹,

Sugier²,

Sreelatha³

et al. 2022

JPD

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Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

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Biases in GWAS – the dog that did not bark

Cited by 9 publications

References 26 publications

Genome-Wide Association Study on Blood Pressure Traits in the Iranian Population Suggests ZBED9 as A New Locus for Hypertension.

Genome-Wide Association Study on Blood Pressure Traits in the Iranian Population Suggests ZBED9 as A New Locus for Hypertension.

Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study

Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson’s Disease

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