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Home > Polygenic risk score prediction of alcohol dependence symptoms across population-based and clinically ascertained samples.

Savage, Jeanne E and Salvatore, Jessica E and Aliev, Fazil and Edwards, Alexis C and Hickman, Matthew and Kendler, Kenneth S and Macleod, John and Latvala, Antti and Loukola, Anu and Kaprio, Jaakko and Rose, Richard J and Chan, Grace and Hesselbrock, Victor and Webb, Bradley T and Adkins, Amy and Bigdeli, Tim B and Riley, Brien P and Dick, Danielle M (2018) Polygenic risk score prediction of alcohol dependence symptoms across population-based and clinically ascertained samples. Alcoholism, Clinical and Experimental Research , 42 , (3) , pp. 520-530.

BACKGROUND: Despite consistent evidence of the heritability of alcohol use disorders (AUDs), few specific genes with an etiological role have been identified. It is likely that AUDs are highly polygenic; however, the etiological pathways and genetic variants involved may differ between populations. The aim of this study was thus to evaluate whether aggregate genetic risk for AUDs differed between clinically ascertained and population-based epidemiological samples.

METHODS: Four independent samples were obtained: 2 from unselected birth cohorts (Avon Longitudinal Study of Parents and Children [ALSPAC], N = 4,304; FinnTwin12 [FT12], N = 1,135) and 2 from families densely affected with AUDs, identified from treatment-seeking patients (Collaborative Study on the Genetics of Alcoholism, N = 2,097; Irish Affected Sib Pair Study of Alcohol Dependence, N = 706). AUD symptoms were assessed with clinical interviews, and participants of European ancestry were genotyped. Genomewide association was conducted separately in each sample, and the resulting association weights were used to create polygenic risk scores in each of the other samples (12 total discovery-validation pairs), and from meta-analyses within sample type. We then tested how well these aggregate genetic scores predicted AUD outcomes within and across sample types.

RESULTS: Polygenic scores derived from 1 population-based sample (ALSPAC) significantly predicted AUD symptoms in another population-based sample (FT12), but not in either clinically ascertained sample. Trend-level associations (uncorrected p < 0.05) were found for polygenic score predictions within sample types but no or negative predictions across sample types. Polygenic scores accounted for 0 to 1% of the variance in AUD symptoms.

CONCLUSIONS: Though preliminary, these results provide suggestive evidence of differences in the genetic etiology of AUDs based on sample characteristics such as treatment-seeking status, which may index other important clinical or demographic factors that moderate genetic influences. Although the variance accounted for by genomewide polygenic scores remains low, future studies could improve gene identification efforts by amassing very large samples, or reducing genetic heterogeneity by informing analyses with other phenotypic information such as sample characteristics. Multiple complementary approaches may be needed to make progress in gene identification for this complex disorder.


Item Type
Article
Publication Type
Irish-related, International, Article
Drug Type
Alcohol
Intervention Type
Screening / Assessment
Date
March 2018
Page Range
pp. 520-530
Volume
42
Number
3
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