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    A Brief Critique of the TATES Procedure
    (Springer, 2018) Aliev, Fazil; Salvatore, Jessica E.; Agrawal, Arpana; Almasy, Laura; Chan, Grace; Edenberg, Howard J.; Hesselbrock, Victor
    The Trait-based test that uses the Extended Simes procedure (TATES) was developed as a method for conducting multivariate GWAS for correlated phenotypes whose underlying genetic architecture is complex. In this paper, we provide a brief methodological critique of the TATES method using simulated examples and a mathematical proof. Our simulated examples using correlated phenotypes show that the Type I error rate is higher than expected, and that more TATES p values fall outside of the confidence interval relative to expectation. Thus the method may result in systematic inflation when used with correlated phenotypes. In a mathematical proof we further demonstrate that the distribution of TATES p values deviates from expectation in a manner indicative of inflation. Our findings indicate the need for caution when using TATES for multivariate GWAS of correlated phenotypes.
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    RISK PREDICTION WITH POLYGENIC RISK SCORES IN MULTI-ETHNIC SAMPLES
    (Elsevier, 2019) Aliev, Fazil; Salvatore, Jessica; Su, Jinni; Kuo, Sally I-Chun; Barr, Peter; Agrawal, Arpana; Cho, Seung Bin
    [No abstract available]
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    Sibling comparisons elucidate the associations between educational attainment polygenic scores and alcohol, nicotine and cannabis
    (Wiley, 2020) Salvatore, Jessica E.; Barr, Peter B.; Stephenson, Mallory; Aliev, Fazil; Kuo, Sally I-Chun; Su, Jinni; Agrawal, Arpana
    Background and Aims The associations between low educational attainment and substance use disorders (SUDs) may be related to a common genetic vulnerability. We aimed to elucidate the associations between polygenic scores for educational attainment and clinical criterion counts for three SUDs (alcohol, nicotine and cannabis). Design Polygenic association and sibling comparison methods. The latter strengthens inferences in observational research by controlling for confounding factors that differ between families. Setting Six sites in the United States. Participants European ancestry participants aged 25 years and older from the Collaborative Study on the Genetics of Alcoholism (COGA). Polygenic association analyses included 5582 (54% female) participants. Sibling comparisons included 3098 (52% female) participants from 1226 sibling groups nested within the overall sample. Measurements Outcomes included criterion counts for DSM-5 alcohol use disorder (AUDSX), Fagerstrom nicotine dependence (NDSX) and DSM-5 cannabis use disorder (CUDSX). We derived polygenic scores for educational attainment (EduYears-GPS) using summary statistics from a large (> 1 million) genome-wide association study of educational attainment. Findings In polygenic association analyses, higher EduYears-GPS predicted lower AUDSX, NDSX and CUDSX [P < 0.01, effect sizes (R-2) ranging from 0.30 to 1.84%]. These effects were robust in sibling comparisons, where sibling differences in EduYears-GPS predicted all three SUDs (P < 0.05, R-2 0.13-0.20%). Conclusions Individuals who carry more alleles associated with educational attainment tend to meet fewer clinical criteria for alcohol, nicotine and cannabis use disorders, and these effects are robust to rigorous controls for potentially confounding factors that differ between families (e.g. socio-economic status, urban-rural residency and parental education).