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Genetic Evidence for the Association between Schizophrenia and Breast Cancer.

ABSTRACT: Objective:To estimate the potential effect of schizophrenia on breast cancer risk in women, we performed a two-sample Mendelian randomization (MR) study. Methods:The instrumental variables comprised 170 uncorrelated and non-pleiotropic single nucleotide polymorphisms (SNPs) that are significantly associated with schizophrenia risk in genome-wide association studies in 105,000 European descent individuals of the Psychiatric Genomics Consortium (http://www.med.unc.edu/pgc/) and the United Kingdom Clozapine Clinic. The association between these SNPs determined schizophrenia and breast cancer risk was estimated in approximately 229,000 European descent females from the Breast Cancer Association Consortium using the inverse-variance weighted and the weighted median MR methods. Results:We found that the genetically-predicted risk of schizophrenia was associated with increased breast cancer risk (under a random-effects model: odds ratio per 1 unit increase in log odds of schizophrenia = 1.04, 95% confidence interval: 1.02-1.06, p = 5.6 × 10-5). Similar significant associations were observed in analyses using a weighted median model and sensitivity analysis excluding six SNPs with genotype imputation score of less than 0.8, as well as analyses stratified by estrogen receptor status of breast cancer. Conclusion:Our findings implicate a modest increased risk for breast cancer in genetically determined schizophrenic females.

SUBMITTER: Shi J

PROVIDER: S-EPMC6402491 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Genetic Evidence for the Association between Schizophrenia and Breast Cancer.

Shi Jiajun J Wu Lang L Zheng Wei W Wen Wanqing W Wang Shuyang S Shu Xiang X Long Jirong J Shen Chen-Yang CY Wu Pei-Ei PE Saloustros Emmanouil E Chang-Claude Jenny J Brenner Hermann H Shu Xiao-Ou XO Cai Qiuyin Q

Journal of psychiatry and brain science 20180808 4

<h4>Objective</h4>To estimate the potential effect of schizophrenia on breast cancer risk in women, we performed a two-sample Mendelian randomization (MR) study.<h4>Methods</h4>The instrumental variables comprised 170 uncorrelated and non-pleiotropic single nucleotide polymorphisms (SNPs) that are significantly associated with schizophrenia risk in genome-wide association studies in 105,000 European descent individuals of the Psychiatric Genomics Consortium (http://www.med.unc.edu/pgc/) and the ...[more]

PMID: 30854469

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Project description:ImportanceUrban life has been proposed as an environmental risk factor accounting for the increased prevalence of schizophrenia in urban areas. An alternative hypothesis is that individuals with increased genetic risk tend to live in urban/dense areas.ObjectiveTo assess whether adults with higher genetic risk for schizophrenia have an increased probability to live in more populated areas than those with lower risk.Design, setting, and participantsFour large, cross-sectional samples of genotyped individuals of European ancestry older than 18 years with known addresses in Australia, the United Kingdom, and the Netherlands were included in the analysis. Data were based on the postcode of residence at the time of last contact with the participants. Community-based samples who took part in studies conducted by the Queensland Institute for Medical Research Berghofer Medical Research Institute (QIMR), UK Biobank (UKB), Netherlands Twin Register (NTR), or QSkin Sun and Health Study (QSKIN) were included. Genome-wide association analysis and mendelian randomization (MR) were included. The study was conducted between 2016 and 2018.ExposuresPolygenic risk scores for schizophrenia derived from genetic data (genetic risk is independently measured from the occurrence of the disease). Socioeconomic status of the area was included as a moderator in some of the models.Main outcomes and measuresPopulation density of the place of residence of the participants determined from census data. Remoteness and socioeconomic status of the area were also tested.ResultsThe QIMR participants (15 544; 10 197 [65.6%] women; mean [SD] age, 54.4 [13.2] years) living in more densely populated areas (people per square kilometer) had a higher genetic loading for schizophrenia (r2 = 0.12%; P = 5.69 × 10-5), a result that was replicated across all 3 other cohorts (UKB: 345 246; 187 469 [54.3%] women; age, 65.7 [8.0] years; NTR: 11 212; 6727 [60.0%] women; age, 48.6 [17.5] years; and QSKIN: 15 726; 8602 [54.7%] women; age, 57.0 [7.9] years). This genetic association could account for 1.7% (95% CI, 0.8%-3.2%) of the schizophrenia risk. Estimates from MR analyses performed in the UKB sample were significant (b = 0.049; P = 3.7 × 10-7 using GSMR), suggesting that the genetic liability to schizophrenia may have a causal association with the tendency to live in urbanized locations.Conclusions and relevanceThe results of this study appear to support the hypothesis that individuals with increased genetic risk tend to live in urban/dense areas and suggest the need to refine the social stress model for schizophrenia by including genetics as well as possible gene-environment interactions.

Project description:BACKGROUND:The mitochondrial genome encodes for thirty-seven proteins, among them thirteen are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process and promoting the production of reactive oxidative species. METHODS:To investigate the association between mitochondrial genetic variation and breast cancer risk, we tested 314 mitochondrial SNPs (mtSNPs), capturing four complexes of the mitochondrial OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,723 breast cancer cases and 3,260 controls from the Multiethnic Cohort Study. RESULTS:We examined the collective set of 314 mtSNPs as well as subsets of mtSNPs grouped by mitochondrial OXPHOS pathway, complexes, and genes, using the sequence kernel association test and adjusting for age, sex, and principal components of global ancestry. We also tested haplogroup associations using unconditional logistic regression and adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. No significant mitochondrial OXPHOS pathway, gene, and haplogroup associations were observed in African Americans, Asian Americans, Latinos, and Native Hawaiians. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with breast cancer risk (P = 0.017, q = 0.102). In mtSNP-subset analysis, the gene MT-CO2 (P = 0.001, q = 0.09) in Complex IV (cytochrome c oxidase) and MT-ND2 (P = 0.004, q = 0.19) in Complex I (NADH dehydrogenase (ubiquinone)) were significantly associated with breast cancer risk. CONCLUSIONS:In summary, our findings suggest that collective mitochondrial genetic variation and particularly in the MT-CO2 and MT-ND2 may play a role in breast cancer risk among European Americans. Further replication is warranted in larger populations and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to breast cancer risk.

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Genetic Evidence for the Association between Schizophrenia and Breast Cancer.

Publications

Genetic Evidence for the Association between Schizophrenia and Breast Cancer.

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