McGrath, J. J. | Search bioRxiv

bioRxiv2018

Spatial gene-by-environment mapping for schizophrenia reveals locale of upbringing effects beyond urban-rural differences

Identification of mechanisms underlying the incidence of psychiatric disorders has been hampered by the difficulty in discovering highly-predictive environmental risk factors. For example, prior efforts have failed to establish environmental effects predicting geospatial clustering of schizophrenia incidence beyond urban-rural differences. Here, we employ a novel statistical framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing (place of residence, ages 0-7 years) and its synergistic effects with genetic liabilities (polygenic risk for schizophrenia). We use this statistical framework to analyze unprecedented geolocation and genotyping data in a case-cohort study of n=24,028 subjects, drawn from the 1.47 million Danish persons born between 1981 and 2005. Using this framework we estimate the effects of upbringing locale (E) and gene-by-locale interactions (GxE). After controlling for potential confounding variables, upbringing at high-risk locales increases the risk for schizophrenia on average by 122%, while GxE modulates genetic risk for schizophrenia on average by 78%. Within the boundaries of Copenhagen (the largest and most densely populated city of Denmark) specific locales vary substantially in their E and GxE effects, with hazard ratios ranging from 0.26 to 9.26 for E and from 0.20 to 5.95 for GxE. This study provides insight into the degree of geospatial clustering of schizophrenia risk, and our novel analytic procedure provides a framework for decomposing variation in geospatial risk into G, E, and GxE components.

epidemiology↗

bioRxiv2017

Paternal-age-related de novo mutations and risk for five disorders

BackgroundThere are well-established epidemiologic associations between advanced paternal age and increased offspring risk for several psychiatric and developmental disorders. These associations are commonly attributed to age-related de novo mutations. However, the actual magnitude of risk conferred by age-related de novo mutations in the male germline is unknown. Quantifying this risk would clarify the clinical and public health significance of delayed paternity.\n\nMethodsUsing results from large, parent-child trio whole-exome-sequencing studies, we estimated the relationship between paternal-age-related de novo single nucleotide variants (dnSNVs) and offspring risk for five disorders: autism spectrum disorders (ASD), congenital heart disease (CHD), neurodevelopmental disorders with epilepsy (EPI), intellectual disability (ID), and schizophrenia (SCZ). Using Danish national registry data, we then investigated the degree to which the epidemiologic association between each disorder and advanced paternal age was consistent with the estimated role of de novo mutations.\n\nResultsIncidence rate ratios comparing dnSNV-based risk to offspring of 45 versus 25-year-old fathers ranged from 1.05 (95% confidence interval 1.01-1.13) for SCZ to 1.29 (95% CI 1.13-1.68) for ID. Epidemiologic estimates of paternal age risk for CHD, ID and EPI were consistent with the dnSNV effect. However, epidemiologic effects for ASDs and SCZ significantly exceeded the risk that could be explained by dnSNVs alone (p<2e-4 for both comparisons).\n\nConclusionIncreasing dnSNVs due to advanced paternal age confer a small amount of offspring risk for psychiatric and developmental disorders. For ASD and SCZ, epidemiologic associations with delayed paternity largely reflect factors that cannot be assumed to increase with age.

genetics↗