ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry

Laura Jean Bierut, Alison M. Goate, Naomi Breslau, Eric O. Johnson, Sarah Bertelsen, Louis Fox, Arpana Agrawal, Kathleen K. Bucholz, Richard Grucza, Victor Hesselbrock, John Kramer, Samuel Kuperman, John Nurnberger, Bernice Porjesz, Nancy L. Saccone, Marc Schuckit, Jay Tischfield, Jen C. Wang, Tatiana Foroud, John P. Rice, Howard J. Edenberg

SUPPLEMENTARY INFORMATION

Supplementary Acknowledgments

The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut, includes ten different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, A. Goate, J. Rice, K. Bucholz); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield); Southwest Foundation (L. Almasy), Howard University (R. Taylor) and Virginia Commonwealth University (D. Dick). Other COGA collaborators include: L. Bauer (University of Connecticut); D. Koller, S. O’Connor, L. Wetherill, X. Xuei (Indiana University); Grace Chan (University of Iowa); N. Manz, M. Rangaswamy (SUNY Downstate); A. Hinrichs, J. Rohrbaugh, J-C Wang (Washington University in St. Louis); A. Brooks (Rutgers University); and F. Aliev (Virginia Commonwealth University). A. Parsian and M. Reilly are the NIAAA Staff Collaborators. 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, currently a consultant with COGA, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10 AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA).

Subject collection for the Family Study of Cocaine Dependence (FSCD) was funded by the National Institute of Drug Abuse (NIDA), R01 DA13423 to L.J. Bierut. Analysis of the FSCD data was supported through NIDA grants R01 DA019963 and K02 DA021237, both to L.J. Bierut.

The Collaborative Genetic Study of Nicotine Dependence (COGEND) project is a collaborative research group and part of the NIDA Genetics Consortium. Subject collection was supported by NIH grant P01 CA089392 (L.J. Bierut) from the National Cancer Institute. The authors thank Heidi Kromrei and Tracey Richmond for their assistance in data collection. Phenotypic and genotypic data are stored in the NIDA Center for Genetic Studies (NCGS) at http://zork.wustl.edu/ under NIDA Contract HHSN271200477451C (J. Tischfield and J. Rice). Lead investigators directing data collection are L.J. Bierut, N. Breslau, D. Hatsukami, and E.O. Johnson.

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Supplementary Table 1. Adjusted odds ratios estimates by ethnicity from multiple logistic regression modeling of the association of rs1229984 with DSM-IV alcohol dependence.

Study
COGA / COGEND / FSCD
Ethnicity / Model Term / OR (95% CI) / p / OR (95% CI) / p / OR (95% CI) / p
EA / rs1229984
GG
AG & AA / REF
0.25 (0.12, 0.48) / --
5.97 x 10–5 / REF
0.38 (0.23, 0.63) / --
2.19 x 10–4 / REF
0.29 (0.10, 0.85) / --
2.32 x 10–2
Sex
Male
Female / REF
0.18 (0.13, 0.25) / --
<1.00 x 10–15 / REF
0.56 (0.45, 0.70) / --
2.10 x 10–7 / REF
0.54 (0.33, 0.88) / --
1.43 x 10–2
Age, years
1st Quartile
2nd Quartile
3rd Quartile
4th Quartile / REF
1.61 (0.97, 2.70)
0.47 (0.29, 0.76)
0.31 (0.19, 0.50) / --
6.78 x 10–2
2.08 x 10–3
1.95 x 10–6 / REF
0.93 (0.69, 1.25)
1.11 (0.81, 1.53)
1.07 (0.79, 1.45) / --
6.34 x 10–1
5.17 x 10–1
6.74 x 10–1 / REF
1.13 (0.56, 2.31)
0.97 (0.45, 2.09)
1.02 (0.51, 2.05) / --
7.29 x 10–1
9.35 x 10–1
9.50 x 10–1
FTND Nicotine Dependence
Never Smoker
Not Nicotine Dependent
Nicotine Dependent / REF
5.33 (3.48, 8.26)
18.29 (12.32, 27.67) / --
3.33 x 10–14
<1.00 x 10–15 / NA
REF
1.48 (1.19, 1.85) / --
--
5.57 x 10–4 / REF
5.84 (3.22, 10.58)
10.02 (5.20, 19.28) / --
5.38 x 10–12
5.79 x 10–9
DSM-IV Cocaine Dependence
Non-dependent
Dependent / REF
244.17 (34.14, >99.99) / --
1.23 x 10–4 / REF
3.78 (2.59, 5.50) / --
4.13 x 10–12 / REF
10.60 (5.89, 19.10) / --
2.32 x 10–2
AA / rs1229984
GG
AG & AA / REF
0.37 (0.06, 1.89) / --
2.48 x 10–1 / REF
0.47 (0.10, 2.23) / --
3.42 x 10–1 / REF
0.40 (0.13, 1.28) / --
1.24 x 10–1
Sex
Male
Female / REF
0.20 (0.10, 0.40) / --
9.19 x 10–6 / REF
0.32 (0.22, 0.48) / --
2.04 x 10–8 / REF
0.45 (.29, 0.69) / --
2.83 x 10–4
Age, years
1st Quartile
2nd Quartile
3rd Quartile
4th Quartile / REF
0.78 (0.29, 2.09)
1.09 (0.39, 3.06)
0.94 (0.38, 2.38) / --
6.21 x 10–1
8.75 x 10–1
9.03 x 10–1 / REF
1.29 (0.74, 2.25)
1.32 (0.73, 2.39)
1.18 (0.67, 2.07) / --
3.61 x 10–1
3.55 x 10–1
5.67 x 10–1 / REF
0.79 (0.42, 1.47)
1.24 (0.66, 2.37)
0.70 (0.37, 1.30) / --
4.48 x 10–1
5.12 x 10–1
2.53 x 10–1
FTND Nicotine Dependence
Never Smoker
Not Nicotine Dependent
Nicotine Dependent / REF
9.14 (4.16, 21.18)
33.63 (14.18, 88.60) / --
9.67 x 10–8
2.47 x 10–1 / NA
REF
1.39 (0.91, 2.12) / --
1.32 x 10–1 / REF
2.48 (1.34, 4.57)
4.84 (2.67, 8.78) / --
3.77 x 10–3
2.18 x 10–7
DSM-IV Cocaine Dependence
Non-dependent
Dependent / REF
166.63 (22.89, >99.99) / --
1.92 x 10–4 / REF
3.56 (2.12, 5.99) / --
1.54 x 10–6 / REF
7.95 (4.75, 13.32) / --
3.33 x 10–15

AA = African American; EA = European American; OR = Odds Ratio; CI = Confidence Interval; REF = Reference Level; NA = Not Applicable.

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Supplementary Table 2. Association of rs1229984 with DSM-IV alcohol dependence and maximum drinks consumed in a 24-hour period.

Outcome
MAF / DSM-IV Alcohol Dependencea / Maximum Drinks in 24-hour periodb
Ethnicity / N / OR (95% CI) / p / N / β (95% CI) / p
COGA / EA / 0.03 / 1250 / 0.26 (0.13, 0.51) / 9.92 x 10–5 / 1246 / –0.40 (–0.56, –0.24) / 1.47 x 10–6
AA / 0.01 / 428 / 0.26 (0.04, 1.76) / 1.69 x 10–1 / 425 / –0.21 (–0.66, 0.24) / 3.62 x 10–1
COGEND / EA / 0.04 / 1981 / 0.38 (0.23, 0.64) / 2.53 x 10–4 / 1981 / –0.22 (–0.31, –0.12) / 1.06 x 10–5
AA / 0.01 / 685 / 0.48 (0.10, 2.27) / 3.51 x 10–1 / 685 / 0.01 (–0.40, 0.42) / 9.52 x 10–1
FSCD / EA / 0.03 / 558 / 0.33 (0.11, 0.95) / 3.94 x 10–2 / 550 / –0.20 (–0.45, 0.06) / 1.34 x 10–1
AA / 0.02 / 608 / 0.41 (0.13, 1.28) / 1.25 x 10–1 / 588 / –0.70 (–1.11, –0.29) / 9.35 x 10–4
Meta-Analysis / EA / 3789 / 0.33 (0.22, 0.48) / 1.57 x 10–8 / 3777 / –0.26 (–0.34, –0.18) / 1.32 x 10–10
AA / 1721 / 0.39 (0.17, 090) / 2.70 x 10–2 / 1698 / –0.30 (–0.55, –0.06) / 1.49 x 10–2
Combined / 5510 / 0.33 (0.24, 0.47) / 3.90 x 10–10 / 5475 / –0.28 (–0.36, –0.20) / 7.42 x 10–12

aLogistic regression adjusted for principal components, sex, age (in quartiles), nicotine dependence, and cocaine dependence.

bLinear regression of the log transformed number of drinks adjusted for principal components, sex, age (in quartiles), nicotine dependence, and cocaine dependence.

AA=African American; EA=European American; MAF=minor allele frequency; OR=odds ratio; CI=confidence interval.
Supplementary Table 3. Unadjusted association results for rs1229984 with DSM-IV alcohol dependence and maximum drinks consumed in a 24-hour period

Outcome
MAF / DSM-IV Alcohol Dependencea / Maximum Drinks in 24-hour periodb
Ethnicity / N / OR (95% CI) / p / N / β (95% CI) / p
COGA / EA / 0.03 / 1,354 / 0.33 (0.21, 0.52) / 1.63 x 10–6 / 1,350 / –0.59 (–0.82, –0.37) / 2.26 x 10–7
AA / 0.01 / 446 / 0.44 (0.15, 1.34) / 1.50 x 10–1 / 443 / –0.56 (–1.18, 0.06) / 7.78 x 10–2
COGEND / EA / 0.04 / 1,981 / 0.44 (0.27, 0.73) / 1.24 x 10–3 / 1,981 / –0.19 (–0.30, –0.08) / 8.65 x 10–4
AA / 0.01 / 685 / 0.49 (0.11, 2.17) / 3.46 x 10–1 / 685 / –0.03 (–0.49, 0.43) / 9.01 x 10–1
FSCD / EA / 0.03 / 558 / 0.72 (0.35, 1.46) / 3.60 x 10–1 / 550 / –0.18 (–0.53, 0.16) / 3.00 x 10–1
AA / 0.02 / 608 / 0.58 (0.22, 1.55) / 2.77 x 10–1 / 588 / –0.60 (–1.13, –0.07) / 2.57 x 10–2
Meta-Analysis / EA / 3,893 / 0.42 (0.31, 0.57) / 2.02 x 10–8 / 3,881 / –0.28 (–0.37, –0.18) / 4.88 x 10–8
AA / 1,739 / 0.51 (0.26, 0.99) / 4.53 x 10–2 / 1,716 / –0.35 (–0.65, –0.04) / 2.61 x 10–2
Combined / 5,632 / 0.44 (0.33, 0.57) / 2.92 x 10–9 / 5,597 / –0.28 (–0.38, –0.19) / 4.21 x 10–9

aLogistic regression with no covariates.

bLinear regression of the log transformed number of drinks with no covariates.

AA=African American; EA=European American; MAF=minor allele frequency; OR=Odds Ratio; CI=confidence interval.


Supplementary Table 4. Association results for rs1229984 with DSM-IV alcohol dependence and maximum drinks in a 24-hour period, adjusted for age and sex

Outcome
MAF / DSM-IV Alcohol Dependencea / Maximum Drinks in 24-hour periodb
Ethnicity / N / OR (95% CI) / p / N / β (95% CI) / p
COGA / EA / 0.03 / 1,354 / 0.34 (0.20, 0.58) / 7.45 x 10–5 / 1,350 / –0.41 (–0.59, –0.23) / 1.29 x 10–5
AA / 0.01 / 446 / 0.29 (0.09, 0.97) / 4.47 x 10–2 / 443 / –0.66 (–1.22, –0.10) / 2.09 x 10–2
COGEND / EA / 0.04 / 1,981 / 0.43 (0.26, 0.70) / 8.29 x10–4 / 1,981 / –0.21 (–0.31, –0.11) / 3.00 x10–5
AA / 0.01 / 685 / 0.57 (0.13, 2.59) / 4.67 x10–1 / 685 / 0.04 (–0.38, 0.46) / 8.51 x10–1
FSCD / EA / 0.03 / 558 / 0.71 (0.34, 1.45) / 3.41 x 10–1 / 550 / –0.18 (–0.52, 0.15) / 2.89 x 10–1
AA / 0.02 / 608 / 0.62 (0.23, 1.69) / 3.50 x 10–1 / 588 / –0.57 (–1.08, –0.05) / 3.05 x 10–2
Meta-Analysis / EA / 3,893 / 0.44 (0.32, 0.60) / 4.14 x 10–7 / 3,881 / –0.25 (–0.34, –0.17) / 2.49 x 10–9
AA / 1,739 / 0.48 (0.24, 0.94) / 3.30 x 10–2 / 1,716 / –0.31 (–0.59, –0.03) / 2.87 x 10–2
Combined / 5,632 / 0.44 (0.33, 0.59) / 4.05 x 10–8 / 5,597 / –0.24 (–0.32, –0.16) / 3.01 x 10–9

aLogistic regression adjusted for sex and age (in quartiles).

bLinear regression of the log transformed number of drinks adjusted for sex and age (in quartiles).

AA=African American; EA=European American; MAF=minor allele frequency; OR=Odds Ratio; CI=confidence interval.

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