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; 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

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, Towfique Raj, Marc Schuckit, Denise M. ScottRobert E. Taylor, Jay Tischfield, Ahmad R. Hariri, Howard J. Edenberg, Arpana Agrawal, Ryan Bogdan, Bernice Porjesz, Alison M. Goate, Tatiana Foroud

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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.

Original language	English
Article number	e12579
Journal	Genes, Brain and Behavior
Volume	18
Issue number	6
DOIs	https://doi.org/10.1111/gbb.12579
State	Published - Jul 2019

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

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10.1111/gbb.12579

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Lai, D., Wetherill, L., Bertelsen, S., Carey, C. E., Kamarajan, C., Kapoor, M., Meyers, J. L., Anokhin, A. P., Bennett, D. A., Bucholz, K. K., Chang, K. K., De Jager, P. L., Dick, D. M., Hesselbrock, V., Kramer, J., Kuperman, S., Nurnberger, J. I., Raj, T., Schuckit, M., ... Foroud, T. (2019). Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria. Genes, Brain and Behavior, 18(6), Article e12579. https://doi.org/10.1111/gbb.12579

@article{92bc76e534864418bcb1d677b13f051a,

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

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",

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

note = "Funding Information: A.A. receives additional funding support from NIDA (DA032573). A.P.A. receives additional funding support from NIH (HD083614, DA040716, DA038834). R.B. receives additional funding support from NIH (AG052564, HD083614, AG045231). C.E.C. received additional funding support from the National Science Foundation (DGE-1143954) and the Mr and Mrs Spencer T. Olin Fellowship Program. D.M.D. receives additional funding from National Institute on Alcohol Abuse and Alcoholism (K02AA018755). A.R.H. receives additional funding support from NIH (R01-DA031579 and R01-AG049789). J.L.M. receives additional funding support from NIDA (K01DA037914). Funding Information: This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract number HHSN268201200008I. The Duke Neurogenetics Study is supported by Duke University and the National Institutes of Health (NIH) (R01-DA033369). A.A. receives additional funding support from NIDA (DA032573). A.P.A. receives additional funding support from NIH (HD083614, DA040716, DA038834). R.B. receives additional funding support from NIH (AG052564, HD083614, AG045231). C.E.C. received additional funding support from the National Science Foundation (DGE-1143954) and the Mr and Mrs Spencer T. Olin Fellowship Program. D.M.D. receives additional funding from National Institute on Alcohol Abuse and Alcoholism (K02AA018755). A.R.H. receives additional funding support from NIH (R01-DA031579 and R01-AG049789). J.L.M. receives additional funding support from NIDA (K01DA037914). A.M.G. is listed as an inventor on issued U.S. Patent 8080371, ?Markers for Addiction? covering the use of certain variants in determining the diagnosis, prognosis and treatment of addiction. J.I.N. receives support as an investigator for Janssen. No other authors report biomedical financial interests or potential conflicts of interest. Funding Information: National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse (NIDA), Grant/Award Number: U10AA008401; National Institute on Drug Abuse, Grant/Award Numbers: DA032573, K01DA037914; NIDA; National Institutes of Health (NIH), Grant/Award Numbers: R01-AG049789, R01-DA031579, AG045231, HD083614, AG052564, DA038834, DA040716; National Science Foundation, Grant/Award Number: DGE-1143954; NIDA; Duke University; NIH, Grant/Award Numbers: AG045231, AG052564, DA038834, DA040716, HD083614, HHSN268201200008I, K02AA018755, R01-AG049789, R01-DA031579, R01-DA033369 Funding Information: We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, P. Michael Conneally, Raymond Crowe and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). Funding Information: The Duke Neurogenetics Study is supported by Duke University and the National Institutes of Health (NIH) (R01-DA033369). Funding Information: Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract number HHSN268201200008I. Publisher Copyright: {\textcopyright} 2019 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society",

year = "2019",

month = jul,

doi = "10.1111/gbb.12579",

language = "English",

volume = "18",

journal = "Genes, Brain and Behavior",

issn = "1601-1848",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "6",

}

Lai, D, Wetherill, L, Bertelsen, S, Carey, CE, Kamarajan, C, Kapoor, M, Meyers, JL, Anokhin, AP, Bennett, DA, Bucholz, KK, Chang, KK, De Jager, PL, Dick, DM, Hesselbrock, V, Kramer, J, Kuperman, S, Nurnberger, JI, Raj, T, Schuckit, M, Scott, DM, Taylor, RE, Tischfield, J, Hariri, AR, Edenberg, HJ, Agrawal, A, Bogdan, R, Porjesz, B, Goate, AM & Foroud, T 2019, 'Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria', Genes, Brain and Behavior, vol. 18, no. 6, e12579. https://doi.org/10.1111/gbb.12579

TY - JOUR

T1 - Genome-wide association studies of alcohol dependence, DSM-IV criterion count and individual criteria

AU - Lai, Dongbing

AU - Wetherill, Leah

AU - Bertelsen, Sarah

AU - Carey, Caitlin E.

AU - Kamarajan, Chella

AU - Kapoor, Manav

AU - Meyers, Jacquelyn L.

AU - Anokhin, Andrey P.

AU - Bennett, David A.

AU - Bucholz, Kathleen K.

AU - Chang, Katharine K.

AU - De Jager, Philip L.

AU - Dick, Danielle M.

AU - Hesselbrock, Victor

AU - Kramer, John

AU - Kuperman, Samuel

AU - Nurnberger, John I.

AU - Raj, Towfique

AU - Schuckit, Marc

AU - Scott, Denise M.

AU - Taylor, Robert E.

AU - Tischfield, Jay

AU - Hariri, Ahmad R.

AU - Edenberg, Howard J.

AU - Agrawal, Arpana

AU - Bogdan, Ryan

AU - Porjesz, Bernice

AU - Goate, Alison M.

AU - Foroud, Tatiana

N1 - Funding Information: A.A. receives additional funding support from NIDA (DA032573). A.P.A. receives additional funding support from NIH (HD083614, DA040716, DA038834). R.B. receives additional funding support from NIH (AG052564, HD083614, AG045231). C.E.C. received additional funding support from the National Science Foundation (DGE-1143954) and the Mr and Mrs Spencer T. Olin Fellowship Program. D.M.D. receives additional funding from National Institute on Alcohol Abuse and Alcoholism (K02AA018755). A.R.H. receives additional funding support from NIH (R01-DA031579 and R01-AG049789). J.L.M. receives additional funding support from NIDA (K01DA037914). Funding Information: This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract number HHSN268201200008I. The Duke Neurogenetics Study is supported by Duke University and the National Institutes of Health (NIH) (R01-DA033369). A.A. receives additional funding support from NIDA (DA032573). A.P.A. receives additional funding support from NIH (HD083614, DA040716, DA038834). R.B. receives additional funding support from NIH (AG052564, HD083614, AG045231). C.E.C. received additional funding support from the National Science Foundation (DGE-1143954) and the Mr and Mrs Spencer T. Olin Fellowship Program. D.M.D. receives additional funding from National Institute on Alcohol Abuse and Alcoholism (K02AA018755). A.R.H. receives additional funding support from NIH (R01-DA031579 and R01-AG049789). J.L.M. receives additional funding support from NIDA (K01DA037914). A.M.G. is listed as an inventor on issued U.S. Patent 8080371, ?Markers for Addiction? covering the use of certain variants in determining the diagnosis, prognosis and treatment of addiction. J.I.N. receives support as an investigator for Janssen. No other authors report biomedical financial interests or potential conflicts of interest. Funding Information: National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse (NIDA), Grant/Award Number: U10AA008401; National Institute on Drug Abuse, Grant/Award Numbers: DA032573, K01DA037914; NIDA; National Institutes of Health (NIH), Grant/Award Numbers: R01-AG049789, R01-DA031579, AG045231, HD083614, AG052564, DA038834, DA040716; National Science Foundation, Grant/Award Number: DGE-1143954; NIDA; Duke University; NIH, Grant/Award Numbers: AG045231, AG052564, DA038834, DA040716, HD083614, HHSN268201200008I, K02AA018755, R01-AG049789, R01-DA031579, R01-DA033369 Funding Information: We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, P. Michael Conneally, Raymond Crowe and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). Funding Information: The Duke Neurogenetics Study is supported by Duke University and the National Institutes of Health (NIH) (R01-DA033369). Funding Information: Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract number HHSN268201200008I. Publisher Copyright: © 2019 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society

PY - 2019/7

Y1 - 2019/7

N2 - 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.

AB - 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.

KW - DSM-IV alcohol dependence criterion

KW - DSM-IV criterion count

KW - DSM-IV individual criteria

KW - alcohol dependence

KW - event-related theta oscillations

KW - functional magnetic resonance imaging

KW - genome-wide association study

KW - item response analysis

KW - meta-analysis

KW - polygenic risk score

UR - http://www.scopus.com/inward/record.url?scp=85067028100&partnerID=8YFLogxK

U2 - 10.1111/gbb.12579

DO - 10.1111/gbb.12579

M3 - Article

C2 - 31090166

AN - SCOPUS:85067028100

SN - 1601-1848

VL - 18

JO - Genes, Brain and Behavior

JF - Genes, Brain and Behavior

IS - 6

M1 - e12579

ER -

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

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