Polygenic Risk Score Prediction of Alcohol Dependence Symptoms Across Population-Based and Clinically Ascertained Samples.

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Authors: Savage, Jeanne E; Salvatore, Jessica E; Aliev, Fazil; Edwards, Alexis C; Hickman, Matthew; Kendler, Kenneth S; Macleod, John; Latvala, Antti; Loukola, Anu; Kaprio, Jaakko; Rose, Richard J; Chan, Grace; Hesselbrock, Victor; Webb, Bradley T; Adkins, Amy; Bigdeli, Tim B; Riley, Brien P; Dick, Danielle M
Year: 2018
Journal: Alcoholism, clinical and experimental research
PMID: 29405378
DOI: 10.1111/acer.13589
PMCID: PMC5832589

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.

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40	Discussion	Despite these limitations, this study provided modest but consistent evidence across multiple…

Citation	PMID	DOI	Status
Abecasis, GR et al., Nature, 2012, An integrated map of genetic variation from 1,092 human genomes	23128226	10.1038/nature11632	Cited
Adkins, AE et al., Alcohol Clin Exp Res, 2017, Genomewide association study of alcohol dependence identifies risk loci altering ethanol-response behaviors in model organisms	28226201	10.1111/acer.13362	Primary
Ali, MA et al., Psychiatr Genet, 2015, Phenotypic heterogeneity in study populations may significantly confound the results of genetic association studies on alcohol dependence	26368818	10.1097/YPG.0000000000000105	Cited
Aulchenko, YS et al., Bioinformatics, 2007, Genabel: An r library for genome-wide association analysis	17384015	10.1093/bioinformatics/btm108	Cited
Babor, TF et al., Arch Gen Psychiatry, 1992, Types of alcoholics, i. Evidence for an empirically derived typology based on indicators of vulnerability and severity	1637250	10.1001/archpsyc.1992.01820080007002	Cited
Babor, TF et al., Audit: The alcohol use disorders identification test, 2001	—	—	—
Bartoń, K, Mumin: Multi-model inference, 2016	—	—	—
Bates, D et al., 2015, Fitting linear mixed-effects models using lme4	—	—	—
Begleiter, H et al., Alcohol Health & Research World, 1995, The collaborative study on the genetics of alcoholism	31798102	—	Primary
Bergen, SE et al., Twin Res Hum Genet, 2007, Age-related changes in heritability of behavioral phenotypes over adolescence and young adulthood: A meta-analysis	17564500	10.1375/twin.10.3.423	Cited
Blanco, C et al., Drug Alcohol Depend, 2008, Generalizability of clinical trials for alcohol dependence to community samples	18579319	10.1016/j.drugalcdep.2008.05.002	Cited
Blanco, C et al., Drug Alcohol Depend, 2015, Probability and predictors of treatment-seeking for substance use disorders in the U.S	25725934	10.1016/j.drugalcdep.2015.01.031	Cited
Boyd, A et al., Int J Epidemiol, 2013, Cohort profile: The ‘children of the 90s’–the index offspring of the avon longitudinal study of parents and children	22507743	10.1093/ije/dys064	Cited
Bucholz, KK et al., J Stud Alcohol, 1994, A new, semi-structured psychiatric interview for use in genetic linkage studies: A report on the reliability of the ssaga	8189735	10.15288/jsa.1994.55.149	Primary
Champely, S, Pwr: Basic functions for power analysis. R package version 1.1-3, 2015	—	—	—
Chang, CC et al., Gigascience, 2015, Second-generation plink: Rising to the challenge of larger and richer datasets	25722852	10.1186/s13742-015-0047-8	Cited
Chen, W-M et al., The American Journal of Human Genetics, 2007, Family-based association tests for genomewide association scans	17924335	10.1086/521580	Cited
Cloninger, CR et al., Adv Alcohol Subst Abuse, 1988, Genetic heterogeneity and the classification of alcoholism	3066194	10.1300/J251v07n03_02	Cited
Diagnostic and statistical manual of mental disorders : Dsm-iv-tr, 2000	—	—	—
Dick, DM et al., Addiction, 2007, Alcohol dependence with comorbid drug dependence: Genetic and phenotypic associations suggest a more severe form of the disorder with stronger genetic contribution to risk	17567401	10.1111/j.1360-0443.2007.01871.x	Primary
Dick, DM et al., Alcohol Research : Current Reviews, 2012, The impact of gene–environment interaction on alcohol use disorders	23134047	10.35946/arcr.v34.3.06	Cited
Edwards, AC et al., Addiction, 2015, Genomic influences on alcohol problems in a population-based sample of young adults	25439982	10.1111/add.12822	Cited
Edwards, AC et al., Psychol Med, 2013, Alcohol consumption in men is influenced by qualitatively different genetic factors in adolescence and adulthood	23282961	10.1017/S0033291712002917	Cited
Euesden, J et al., Bioinformatics, 2015, Prsice: Polygenic risk score software	25550326	10.1093/bioinformatics/btu848	Cited
Fatemifar, G et al., Hum Mol Genet, 2013, Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances	23704328	10.1093/hmg/ddt231	Cited
Global health risks : Mortality and burden of disease attributable to selected major risks, 2009	—	—	—
Golding, J et al., Paediatr Perinat Epidemiol, 2001, Alspac–the avon longitudinal study of parents and children. I. Study methodology	11237119	10.1046/j.1365-3016.2001.00325.x	Cited
Grant, BF et al., JAMA Psychiatry, 2015, Epidemiology of dsm-5 alcohol use disorder: Results from the national epidemiologic survey on alcohol and related conditions iii	26039070	10.1001/jamapsychiatry.2015.0584	Cited
Hansell, NK et al., Alcoholism: Clinical and Experimental Research, 2009, Can we identify genes for alcohol consumption in samples ascertained for heterogeneous purposes?	19183129	10.1111/j.1530-0277.2008.00890.x	Cited
Hart, AB et al., Alcohol Clin Exp Res, 2015, Alcohol dependence genetics: Lessons learned from genome-wide association studies (gwas) and post-gwas analyses	26110981	10.1111/acer.12792	Cited
Hines, LM et al., Dialogues in Clinical Neuroscience, 2005, Alcoholism: The dissection for endophenotypes	16262210	10.31887/DCNS.2005.7.2/lhines	Cited
Kapoor, M et al., Drug Alcohol Depend, 2014, Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk coga families	24962325	10.1016/j.drugalcdep.2014.05.023	Primary
Kaprio, J et al., Twin Res, 2002, Genetic and environmental factors in health-related behaviors: Studies on finnish twins and twin families	12537860	10.1375/136905202320906101	Cited
Kaprio, J, Twin Res Hum Genet, 2006, Twin studies in finland 2006	17254406	10.1375/183242706779462778	Cited
Kaufmann, CN et al., Soc Psychiatry Psychiatr Epidemiol, 2014, Treatment seeking and barriers to treatment for alcohol use in persons with alcohol use disorders and comorbid mood or anxiety disorders	23900549	10.1007/s00127-013-0740-9	Cited
Kendler, K et al., Molecular Psychiatry, 2012, Evidence for multiple genetic factors underlying the DSM-IV criteria for alcohol dependence	22105626	10.1038/mp.2011.153	Cited
Kuntsche, E et al., Clin Psychol Rev, 2005, Why do young people drink? A review of drinking motives	16095785	10.1016/j.cpr.2005.06.002	Cited
Kuo, P-H et al., Drug and Alcohol Dependence, 2008, Using a factor mixture modeling approach in alcohol dependence in a general population sample	18586414	10.1016/j.drugalcdep.2008.04.018	Cited
Leggio, L et al., Neuropsychol Rev, 2009, Typologies of alcohol dependence. From jellinek to genetics and beyond	19184441	10.1007/s11065-008-9080-z	Cited
Li, Y et al., Genet Epidemiol, 2010, Mach: Using sequence and genotype data to estimate haplotypes and unobserved genotypes	21058334	10.1002/gepi.20533	Cited
Manchia, M et al., PLoS One, 2013, The impact of phenotypic and genetic heterogeneity on results of genome wide association studies of complex diseases	24146854	10.1371/journal.pone.0076295	Cited
Mbarek, H et al., Am J Med Genet B Neuropsychiatr Genet, 2015, The genetics of alcohol dependence: Twin and snp-based heritability, and genome-wide association study based on audit scores	26365420	10.1002/ajmg.b.32379	Cited
Meyers, JL, Human and Molecular Genetics, 2012, Elucidating genetic and environmental influences on alcohol-related phenotypes	—	—	—
Nature, 2009, Common polygenic variation contributes to risk of schizophrenia and bipolar disorder	19571811	10.1038/nature08185	Cited
Nature, 2014, Biological insights from 108 schizophrenia-associated genetic loci	25056061	10.1038/nature13595	Cited
Palmer, RH et al., Drug Alcohol Depend, 2012, The genetics of alcohol dependence: Advancing towards systems-based approaches	22854292	10.1016/j.drugalcdep.2012.07.005	Cited
Prescott, CA et al., Alcohol Clin Exp Res, 2005, The irish affected sib pair study of alcohol dependence: Study methodology and validation of diagnosis by interview and family history	15770118	10.1097/01.alc.0000156085.50418.07	Cited
R: A language and environment for statistical computing, 2015	—	—	—
Results from the 2013 national survey on drug use and health: Summary of national findings, 2014	—	—	—
Salvatore, JE et al., Genes (Basel), 2014, Polygenic scores predict alcohol problems in an independent sample and show moderation by the environment	24727307	10.3390/genes5020330	Cited
Sanchez-Roige, S et al., Genome-wide association study of Alcohol Use Disorder Identification Test (AUDIT) scores in 20,328 research participants of European ancestry, 2017	29058377	10.1111/adb.12574	Cited
Sullivan, PF et al., Nat Rev Genet, 2012, Genetic architectures of psychiatric disorders: The emerging picture and its implications	22777127	10.1038/nrg3240	Cited
Thompson, EA et al., Biometrics, 1990, Pedigree analysis for quantitative traits: Variance components without matrix inversion	2364130	—	Cited
Verhulst, B et al., Psychol Med, 2015, The heritability of alcohol use disorders: A meta-analysis of twin and adoption studies	25171596	10.1017/S0033291714002165	Cited
Wang, JC et al., Mol Psychiatry, 2013, A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies c15orf53	23089632	10.1038/mp.2012.143	Primary
Willer, CJ et al., Bioinformatics, 2010, METAL: fast and efficient meta-analysis of genomewide association scans	20616382	10.1093/bioinformatics/btq340	Cited
Yang, C et al., Hum Genet, 2014, Exploring the genetic architecture of alcohol dependence in african-americans via analysis of a genomewide set of common variants	24297757	10.1007/s00439-013-1399-8	Cited
Yang, J et al., Am J Hum Genet, 2011, Gcta: A tool for genome-wide complex trait analysis	21167468	10.1016/j.ajhg.2010.11.011	Cited
Young-Wolff, KC et al., Clinical Psychology Review, 2011, The influence of gene-environment interactions on alcohol consumption and alcohol use disorders: a comprehensive review	21530476	10.1016/j.cpr.2011.03.005	Cited

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Polygenic contributions to alcohol use and alcohol use disorders across population-based and clinically ascertained samples.	Johnson EC et al.	—	2021	→
Polygenic Scores for ADHD: A Meta-Analysis.	Li JJ et al.	—	2021	→
The associations between polygenic risk, sensation seeking, social support, and alcohol use in adulthood.	Su J et al.	—	2021	→
A Family-Based Genome Wide Association Study of Externalizing Behaviors.	Barr PB et al.	—	2020	→
Recent Efforts to Dissect the Genetic Basis of Alcohol Use and Abuse.	Sanchez-Roige S et al.	—	2020	→
FinnTwin12 Cohort: An Updated Review.	Rose RJ et al.	—	2019	→
Genetics of alcohol use disorder: a review.	Deak JD et al.	—	2019	→
Long-Chain ω-3 Levels Are Associated With Increased Alcohol Sensitivity in a Population-Based Sample of Adolescents.	Edwards AC et al.	—	2019	→
Psychosocial moderation of polygenic risk for cannabis involvement: the role of trauma exposure and frequency of religious service attendance.	Meyers JL et al.	—	2019	→
The Genetic Relationship Between Alcohol Consumption and Aspects of Problem Drinking in an Ascertained Sample.	Johnson EC et al.	—	2019	→
Examining interactions between genetic risk for alcohol problems, peer deviance, and interpersonal traumatic events on trajectories of alcohol use disorder symptoms among African American college students.	Su J et al.	—	2018	→