Evaluating causal associations between previously reported risk factors and epithelial ovarian cancer: a Mendelian randomization analysis

Yarmolinsky, James; Relton, Caroline; Lophatananon, Artitaya; Muir, Kenneth; Menon, Usha; Gentry‐Maharaj, Aleksandra; Walther, Axel; Zheng, Jie; Fasching, Peter A.; Wang, Zheng; Ling, Woo Yin; Chang‐Claude, Jenny; Park, Sung Sup; Choi, Ji Yeob; Park, Boyoung; Smith, George Davey; Martin, Richard M; Lewis, Sarah J.

doi:10.1101/472696

Cited by 4 publications

(3 citation statements)

References 71 publications

(54 reference statements)

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“…28 More than 60 MR studies have been published to date utilizing genetic variants associated with 25OHD to aid causal effect estimation. [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] A deeper understanding of the genetic determinants contributing to variation in circulating vitamin D levels could enable an improved instrumentation of vitamin D in MR studies, allow better genomic prediction of vitamin D levels and provide insights into biological mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci

Manousaki

Mitchell

Dudding

et al. 2020

The American Journal of Human Genetics

170

269

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We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrichment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 3 10 À9 ) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architecture of 25OHD.

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Section: Introductionmentioning

confidence: 99%

Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci

Manousaki

Mitchell

Dudding

et al. 2020

The American Journal of Human Genetics

170

269

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“…Aside from family history of breast or ovarian cancer, high body mass index in adolescence, diagnosis of endometriosis, and taller height, most established risk factors are hormonal or reproductive [1]. A recent Mendelian randomization (MR) study of 13 known observational risk factors only confirmed genetic liability to lifetime smoking and endometriosis as causal [5]. Thus, identification of additional risk factors is crucial for designing prevention strategies and for earlier diagnosis of EOC.…”

Section: Introductionmentioning

confidence: 99%

Bi-directional Mendelian randomization of epithelial ovarian cancer and schizophrenia and uni-directional Mendelian randomization of schizophrenia on circulating 1- or 2-glycerophosphocholine metabolites

Adams

Neuhausen

2019

Molecular Genetics and Metabolism Reports

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Most women with epithelial ovarian cancer (EOC) present with late-stage disease. As a result, globally, EOC is responsible for >150,000 deaths a year. Thus, a better understanding of risk factors for developing EOC is crucial for earlier screening and detection to improve survival. To that effort, there have been suggestions that there is an association of schizophrenia and cancer, possibly because metabolic changes are a hallmark of both cancer and schizophrenia (SZ). Perturbed choline metabolism has been documented in both diseases. Our objective was to use Mendelian randomization to evaluate whether SZ increased risk for developing EOC or the converse, and, whether SZ impacted 1- or 2-glycerophosphocholine (1- or 2-GPC) metabolites. We found that SZ conferred a weak but increased risk for EOC, but not the reverse (no evidence that EOC caused SZ). SZ was also causally associated with lower levels of two 1- or 2-GPC species and with suggestively lower levels in an additional three 1- or 2-GPCs. We postulate that perturbed choline metabolism in SZ may mimic or contribute to a “cholinic” phenotype, as observed in EOC cells.

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“…It is interesting to note that the MR findings on vitamin D and ovarian cancer did not replicate in subsequent MR analyses [194,326]. I speculate that the reason might be attributable to study design difference and the increasing sample size.…”

Section: Making Sense Of the Pan-cancer Approachmentioning

confidence: 92%

On the use of genetic information in causal inference for human complex diseases: a collection of studies on cancers

Ong¹

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The introduction chapter (Chapter 1) starts with a summary of recent progress in genetic epidemiology. The advancement of genotyping technology made it feasible to revisit a 30 years old study design known as Mendelian randomization (MR) where germline genetic variants can be used as natural instruments to assess causality between human complex traits. Here the rationale and technical assumptions required to conduct feasible MR studies were explained. The overall thesis objective and study approaches used in the thesis were also outlined. The final subchapter provides details on the definition of disease phenotypes that will be used throughout the thesis, including the creation of a "pan-cancer" phenotype, a combined cancer outcome of whether a person is diagnosed with any cancer, which was subsequently used in Chapter 4 and 5.In Chapters 2 and 3, I investigated whether MR can be used to infer causality between modifiable risk factors and specific cancers. For Chapter 2, I applied MR to evaluate the link between vitamin D and coffee intake on epithelial ovarian carcinomas (EOC). This was done in a two-sample MR framework where genetic instruments for the risk factor were obtained from public GWAS literature and the cancer GWAS statistics were obtained from the Ovarian Cancer Association Consortium (OCAC). While higher genetically predicted vitamin D reduced the risk of EOC, there was no evidence to support a link between genetically predicted coffee intake and EOC. For Chapter 3, I contrasted and compared the association between alcohol intake with breast and ovarian cancer using both MR and observational analyses. Genetic summary statistics were obtained from the OCAC and BCAC (breast cancer). Previous observational findings show an adverse relationship between alcohol intake and breast cancer susceptibility, however the association was protective on EOC. Our observational data replicate previous findings, with MR estimates showing consistent direction of effect for EOC; while no evidence to support a strong link between alcohol intake and breast cancer risk. Taken altogether, the effect of alcohol on these cancers is likely small if causative at all.In Chapter 4 and 5, I performed MR to evaluate a series of modifiable risk factors on overall cancer outcomes. Using data from the UK Biobank, we constructed an aggregate phenotype allowing us to evaluate whether "modifying specific behaviour (or risk factor) will 3 alter an individual's risk of being diagnosed or dying from cancer". The proof-of-principle MR study using height is shown in Chapter 4, where MR findings are highly concordant with observational findings that taller people have increased risk of developing cancer. Findings for obesity, vitamin D and coffee intake on overall cancer outcomes are further elaborated in Chapter 5.In Chapter 5, the approach undertaken to evaluate these risk factors and cancer were each described in turn, followed by a subchapter to summarise these MR findings. Genetically higher BMI is associated with an increase of being dia...

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Evaluating causal associations between previously reported risk factors and epithelial ovarian cancer: a Mendelian randomization analysis

Cited by 4 publications

References 71 publications

Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci

Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci

Bi-directional Mendelian randomization of epithelial ovarian cancer and schizophrenia and uni-directional Mendelian randomization of schizophrenia on circulating 1- or 2-glycerophosphocholine metabolites

On the use of genetic information in causal inference for human complex diseases: a collection of studies on cancers

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