Brazel, D. M. et al. (2019) Exome chip meta-analysis fine maps causal variants and elucidates the genetic architecture of rare coding variants in smoking and alcohol use. Number of words in abstract: 249Number of words in main text: 3676 Abstract: Background: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences, and contribute to disease risk. Methods: We analyzed ~250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-
Background and aims Cannabis is one of the most commonly used substances among adolescents and young adults.Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. Methods A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. Results The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r 2 > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. Conclusion Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.
Genetic association studies routinely require many thousands of participants to achieve sufficient power, yet accumulation of large well-assessed samples is costly. We describe here an effort to efficiently measure cognitive ability and personality in an online genetic study, Genes for Good. We report on the first 21,550 participants with relevant phenotypic data, 7,458 of whom have been genotyped genome-wide. Measures of crystallized and fluid intelligence reflected a two-dimensional latent ability space, with items demonstrating adequate item-level characteristics. The Big Five Inventory questionnaire revealed the expected five-factor model of personality. Cognitive measures predicted educational attainment over and above personality characteristics, as expected. We found that a genome-wide polygenic score of educational attainment predicted educational level, accounting for 4%, 4%, and 2.7% of the variance in educational attainment, verbal reasoning, and spatial reasoning, respectively. In summary, the online cognitive measures in Genes for Good appear to perform adequately and demonstrate expected associations with personality, education, and an education-based polygenic score. Results indicate that online cognitive assessment is one avenue to accumulate large samples of individuals for genetic research of cognitive ability.
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