Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria

Dongbing Lai; Leah Wetherill; Sarah Bertelsen; Caitlin E Carey; Chella Kamarajan; Manav Kapoor; Jacquelyn L Meyers; Andrey P Anokhin; David A Bennett; Kathleen K Bucholz; Katharine K Chang; Philip L De Jager; Danielle M Dick; Victor Hesselbrock; John Kramer; Samuel Kuperman; John I Nurnberger Jr; Towfique Raj; Marc Schuckit; Denise M Scott; Robert E Taylor; Jay Tischfield; Ahmad R Hariri; Howard J Edenberg; Arpana Agrawal; Ryan Bogdan; Bernice Porjesz; Alison M Goate; Tatiana Foroud

doi:10.1111/gbb.12579

Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria

Genes Brain Behav. 2019 Jul;18(6):e12579. doi: 10.1111/gbb.12579. Epub 2019 Jun 4.

Authors

Dongbing Lai¹, Leah Wetherill¹, Sarah Bertelsen², Caitlin E Carey³, Chella Kamarajan⁴, Manav Kapoor², Jacquelyn L Meyers⁴, Andrey P Anokhin⁵, David A Bennett⁶, Kathleen K Bucholz⁵, Katharine K Chang³, Philip L De Jager^{7

8}, Danielle M Dick⁹, Victor Hesselbrock¹⁰, John Kramer¹¹, Samuel Kuperman¹¹, John I Nurnberger Jr^{1

12}, Towfique Raj², Marc Schuckit¹³, Denise M Scott^{14

15}, Robert E Taylor¹⁶, Jay Tischfield¹⁷, Ahmad R Hariri¹⁸, Howard J Edenberg^{1

19}, Arpana Agrawal⁵, Ryan Bogdan³, Bernice Porjesz⁴, Alison M Goate², Tatiana Foroud¹

Affiliations

¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
² Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, New York.
³ BRAIN Lab, Department of Psychological and Brain Sciences, Washington University School of Medicine, St. Louis, Missouri.
⁴ Henri Begleiter Neurodynamics Lab, Department of Psychiatry, Downstate Medical Center, State University of New York, Brooklyn, New York.
⁵ Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
⁶ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
⁷ Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts.
⁸ Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts.
⁹ Department of Psychology, Virginia Commonwealth University, Richmond, Virginia.
¹⁰ Department of Psychiatry, University of Connecticut, Farmington, Connecticut.
¹¹ Department of Psychiatry, Roy Carver College of Medicine, University of Iowa, Iowa City, Iowa.
¹² Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana.
¹³ Department of Psychiatry, San Diego Medical School, University of California, San Diego, California.
¹⁴ Department of Pediatrics, Howard University, Washington, District of Columbia.
¹⁵ Department of Human Genetics, Howard University, Washington, District of Columbia.
¹⁶ Department of Pharmacology, Howard University, Washington, District of Columbia.
¹⁷ Department of Genetics, Rutgers University, Newark, New Jersey.
¹⁸ Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, North Carolina.
¹⁹ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.

Abstract

Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P < .01; 0.61%-1.82% of variance). Identified novel variants (ie, rs1912461, rs61826952) were associated with differential central evoked theta power (loss - gain; P = .0037) and reward-related ventral striatum reactivity (P = .008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.

Keywords: DSM-IV alcohol dependence criterion; DSM-IV criterion count; DSM-IV individual criteria; alcohol dependence; event-related theta oscillations; functional magnetic resonance imaging; genome-wide association study; item response analysis; meta-analysis; polygenic risk score.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adolescent
Adult
Alcohol Dehydrogenase / genetics
Alcoholism / genetics*
Alcoholism / physiopathology
Black or African American / genetics
Diagnostic and Statistical Manual of Mental Disorders
Female
Humans
Male
Polymorphism, Single Nucleotide*
Reward
Theta Rhythm
Ventral Striatum / physiopathology
White People / genetics

Substances

ADH1B protein, human
Alcohol Dehydrogenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding