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1. Evaluating risk for alcohol use disorder: Polygenic risk scores and family history.

Author: Lai, Dongbing, Lai, Dongbing, Johnson, Emma C, Colbert, Sarah, Pandey, Gayathri, Chan, Grace, Bauer, Lance, Francis, Meredith W, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuang, Weipeng, Kuo, Sally, Kuperman, Samuel, Liu, Yunlong, McCutcheon, Vivia, Pang, Zhiping, Plawecki, Martin H, Schuckit, Marc, Tischfield, Jay, Wetherill, Leah, Zang, Yong, Edenberg, Howard J, Porjesz, Bernice, Agrawal, Arpana, Foroud, Tatiana, Lai, Dongbing, Lai, Dongbing, Johnson, Emma C, Colbert, Sarah, Pandey, Gayathri, Chan, Grace, Bauer, Lance, Francis, Meredith W, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuang, Weipeng, Kuo, Sally, Kuperman, Samuel, Liu, Yunlong, McCutcheon, Vivia, Pang, Zhiping, Plawecki, Martin H, Schuckit, Marc, Tischfield, Jay, Wetherill, Leah, Zang, Yong, Edenberg, Howard J, Porjesz, Bernice, Agrawal, Arpana, and Foroud, Tatiana
Abstract: BackgroundEarly identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM-5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD.MethodsWe studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM-5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM-IV alcohol dependence or DSM-5 AUD and 1616 were alcohol-exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first-degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH-). PRS were derived from a meta-analysis of a genome-wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity.ResultsAUD cases had higher PRS than controls with PRS increasing as the number of DSM-5 diagnostic criteria increased (p-values ≤ 1.85E-05 ) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p-value = 7.57E-08 ) and 1.86 (95% CI: 1.35 to 2.56, p-value = 1.32E-04 ) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first-degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM-5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH?
Published: 2022

2. Gene-based polygenic risk scores analysis of alcohol use disorder in African Americans

Author: Lai, Dongbing, Lai, Dongbing, Schwantes-An, Tae-Hwi, Abreu, Marco, Chan, Grace, Hesselbrock, Victor, Kamarajan, Chella, Liu, Yunlong, Meyers, Jacquelyn L, Nurnberger, John I, Plawecki, Martin H, Wetherill, Leah, Schuckit, Marc, Zhang, Pengyue, Edenberg, Howard J, Porjesz, Bernice, Agrawal, Arpana, Foroud, Tatiana, Lai, Dongbing, Lai, Dongbing, Schwantes-An, Tae-Hwi, Abreu, Marco, Chan, Grace, Hesselbrock, Victor, Kamarajan, Chella, Liu, Yunlong, Meyers, Jacquelyn L, Nurnberger, John I, Plawecki, Martin H, Wetherill, Leah, Schuckit, Marc, Zhang, Pengyue, Edenberg, Howard J, Porjesz, Bernice, Agrawal, Arpana, and Foroud, Tatiana
Abstract: Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within the boundaries of these genes, we proposed a novel gene-based PRS framework (PRSgene) by using variants located within disease-associated genes. Using the AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and the EA GWAS of problematic alcohol use as the discovery GWAS, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRSgene calculated using these variants were significantly associated with AUD in three AA target datasets (P-values ranged from 7.61E-05 to 6.27E-03; Betas ranged from 0.15 to 0.21) and outperformed PRS calculated using all variants (P-values ranged from 7.28E-03 to 0.16; Betas ranged from 0.06 to 0.18). PRSgene were also associated with AUD in an EA target dataset (P-value = 0.02, Beta = 0.11). In AA, individuals in the highest PRSgene decile had an odds ratio of 1.76 (95% CI: 1.32-2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving the synaptic system, which are known to be AUD-related. In addition, 26 genes were targets of drugs used to treat AUD or other diseases that might be considered for repurposing to treat AUD. Our study demonstrated that the gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into AUD genetics.
Published: 2022

3. Do personality characteristics predict future alcohol problems after considering current demography, substance use and alcohol response?

Author: Schuckit, Marc A, Schuckit, Marc A, Smith, Tom L, Danko, George, Bucholz, Kathleen K, Hesselbrock, Victor, Hesselbrock, Michie, Kuperman, Samuel, Kramer, John, Nurnberger, John I, Lai, Dongbing, Chan, Grace, Kamarajan, Chella, Kuo, Sally, Dick, Danielle M, Tear, Jake, Mendoza, Lee A, Edenberg, Howard J, Porjesz, Bernice, Schuckit, Marc A, Schuckit, Marc A, Smith, Tom L, Danko, George, Bucholz, Kathleen K, Hesselbrock, Victor, Hesselbrock, Michie, Kuperman, Samuel, Kramer, John, Nurnberger, John I, Lai, Dongbing, Chan, Grace, Kamarajan, Chella, Kuo, Sally, Dick, Danielle M, Tear, Jake, Mendoza, Lee A, Edenberg, Howard J, and Porjesz, Bernice
Abstract: BackgroundSeveral personality traits predict future alcohol problems but also relate to demographic and substance-related variables that themselves correlate with later adverse alcohol outcomes. Few prospective studies have evaluated whether the personality measures predict alcohol problems after considering current demography and substance related variables.MethodsData from 414 drinkers without alcohol use disorder (AUD) from the Collaborative Study on the Genetics of Alcoholism (average age 20, 44% male) were followed over an average of nine years. Time 1 (baseline) demography, AUD family history (FH), substance use and problems, and psychiatric histories were gathered using a standardized interview, the Level of Response (LR) to alcohol was measured by the Self-Report of the Effects of alcohol (SRE) questionnaire, and seven personality dimensions were extracted from the NEO Five-Factor Personality, Barratt and Zuckerman scales. Analyses involved product-moment correlations of each baseline measure with the highest number of DSM-IV AUD criteria endorsed in any follow-up period, and hierarchical regression analyses evaluated if the personality domains added significantly to the prediction of the outcome after adjusting for other baseline variables.ResultsSignificant correlations to the outcome were observed for baseline age, sex, length of follow-up, AUD family history, past cannabis use, and all alcohol-related baseline variables, including SRE-based Level of Response, but not prior mood or anxiety disorders. All personality characteristics except extraversion also correlated with outcomes. A hierarchical regression analysis that included all relevant personality scores together demonstrated significant contributions to the prediction of future alcohol problems for demography in Step 1, demography and most baseline alcohol items, including response level, in Step 2, and cannabis use in Step 3, after which demography, Level of Response, baseline alcohol problems, c
Published: 2023

4. Predicting Alcohol-Related Memory Problems in Older Adults: A Machine Learning Study with Multi-Domain Features.

Author: Kamarajan, Chella, Kamarajan, Chella, Pandey, Ashwini K, Chorlian, David B, Meyers, Jacquelyn L, Kinreich, Sivan, Pandey, Gayathri, Subbie-Saenz de Viteri, Stacey, Zhang, Jian, Kuang, Weipeng, Barr, Peter B, Aliev, Fazil, Anokhin, Andrey P, Plawecki, Martin H, Kuperman, Samuel, Almasy, Laura, Merikangas, Alison, Brislin, Sarah J, Bauer, Lance, Hesselbrock, Victor, Chan, Grace, Kramer, John, Lai, Dongbing, Hartz, Sarah, Bierut, Laura J, McCutcheon, Vivia V, Bucholz, Kathleen K, Dick, Danielle M, Schuckit, Marc A, Edenberg, Howard J, Porjesz, Bernice, Kamarajan, Chella, Kamarajan, Chella, Pandey, Ashwini K, Chorlian, David B, Meyers, Jacquelyn L, Kinreich, Sivan, Pandey, Gayathri, Subbie-Saenz de Viteri, Stacey, Zhang, Jian, Kuang, Weipeng, Barr, Peter B, Aliev, Fazil, Anokhin, Andrey P, Plawecki, Martin H, Kuperman, Samuel, Almasy, Laura, Merikangas, Alison, Brislin, Sarah J, Bauer, Lance, Hesselbrock, Victor, Chan, Grace, Kramer, John, Lai, Dongbing, Hartz, Sarah, Bierut, Laura J, McCutcheon, Vivia V, Bucholz, Kathleen K, Dick, Danielle M, Schuckit, Marc A, Edenberg, Howard J, and Porjesz, Bernice
Abstract: Memory problems are common among older adults with a history of alcohol use disorder (AUD). Employing a machine learning framework, the current study investigates the use of multi-domain features to classify individuals with and without alcohol-induced memory problems. A group of 94 individuals (ages 50-81 years) with alcohol-induced memory problems (the memory group) were compared with a matched control group who did not have memory problems. The random forests model identified specific features from each domain that contributed to the classification of the memory group vs. the control group (AUC = 88.29%). Specifically, individuals from the memory group manifested a predominant pattern of hyperconnectivity across the default mode network regions except for some connections involving the anterior cingulate cortex, which were predominantly hypoconnected. Other significant contributing features were: (i) polygenic risk scores for AUD, (ii) alcohol consumption and related health consequences during the past five years, such as health problems, past negative experiences, withdrawal symptoms, and the largest number of drinks in a day during the past twelve months, and (iii) elevated neuroticism and increased harm avoidance, and fewer positive "uplift" life events. At the neural systems level, hyperconnectivity across the default mode network regions, including the connections across the hippocampal hub regions, in individuals with memory problems may indicate dysregulation in neural information processing. Overall, the study outlines the importance of utilizing multidomain features, consisting of resting-state brain connectivity data collected ~18 years ago, together with personality, life experiences, polygenic risk, and alcohol consumption and related consequences, to predict the alcohol-related memory problems that arise in later life.
Published: 2023

5. Diagnostic Criteria for Identifying Individuals at High Risk of Progression From Mild or Moderate to Severe Alcohol Use Disorder

Author: Miller, Alex P, Miller, Alex P, Kuo, Sally I-Chun, Johnson, Emma C, Tillman, Rebecca, Brislin, Sarah J, Dick, Danielle M, Kamarajan, Chella, Kinreich, Sivan, Kramer, John, McCutcheon, Vivia V, Plawecki, Martin H, Porjesz, Bernice, Schuckit, Marc A, Salvatore, Jessica E, Edenberg, Howard J, Bucholz, Kathleen K, Meyers, Jaquelyn L, Agrawal, Arpana, Hesselbrock, Victor, Foroud, Tatiana, Liu, Yunlong, Kuperman, Samuel, Pandey, Ashwini K, Bierut, Laura J, Rice, John, Tischfield, Jay A, Hart, Ronald P, Almasy, Laura, Goate, Alison, Slesinger, Paul, Scott, Denise M, Bauer, Lance O, Nurnberger, John I, Wetherill, Leah, Xuei, Xiaoling, Lai, Dongbing, O'Connor, Sean J, Chan, Grace, Chorlian, David B, Zhang, Jian, Barr, Peter B, Pandey, Gayathri, Mullins, Niamh, Anokhin, Andrey P, Hartz, Sarah, Saccone, Scott, Moore, Jennifer C, Aliev, Fazil, Pang, Zhiping, Merikangas, Alison, Chin, Hemin, Parsian, Abbas, Miller, Alex P, Miller, Alex P, Kuo, Sally I-Chun, Johnson, Emma C, Tillman, Rebecca, Brislin, Sarah J, Dick, Danielle M, Kamarajan, Chella, Kinreich, Sivan, Kramer, John, McCutcheon, Vivia V, Plawecki, Martin H, Porjesz, Bernice, Schuckit, Marc A, Salvatore, Jessica E, Edenberg, Howard J, Bucholz, Kathleen K, Meyers, Jaquelyn L, Agrawal, Arpana, Hesselbrock, Victor, Foroud, Tatiana, Liu, Yunlong, Kuperman, Samuel, Pandey, Ashwini K, Bierut, Laura J, Rice, John, Tischfield, Jay A, Hart, Ronald P, Almasy, Laura, Goate, Alison, Slesinger, Paul, Scott, Denise M, Bauer, Lance O, Nurnberger, John I, Wetherill, Leah, Xuei, Xiaoling, Lai, Dongbing, O'Connor, Sean J, Chan, Grace, Chorlian, David B, Zhang, Jian, Barr, Peter B, Pandey, Gayathri, Mullins, Niamh, Anokhin, Andrey P, Hartz, Sarah, Saccone, Scott, Moore, Jennifer C, Aliev, Fazil, Pang, Zhiping, Merikangas, Alison, Chin, Hemin, and Parsian, Abbas
Abstract: ImportanceCurrent Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) diagnoses of substance use disorders rely on criterion count-based approaches, disregarding severity grading indexed by individual criteria.ObjectiveTo examine correlates of alcohol use disorder (AUD) across count-based severity groups (ie, mild, moderate, mild-to-moderate, severe), identify specific diagnostic criteria indicative of greater severity, and evaluate whether specific criteria within mild-to-moderate AUD differentiate across relevant correlates and manifest in greater hazards of severe AUD development.Design, setting, and participantsThis cohort study involved 2 cohorts from the family-based Collaborative Study on the Genetics of Alcoholism (COGA) with 7 sites across the United States: cross-sectional (assessed 1991-2005) and longitudinal (assessed 2004-2019). Statistical analyses were conducted from December 2022 to June 2023.Main outcomes and measuresSociodemographic, alcohol-related, psychiatric comorbidity, brain electroencephalography (EEG), and AUD polygenic score measures as correlates of DSM-5 AUD levels (ie, mild, moderate, severe) and criterion severity-defined mild-to-moderate AUD diagnostic groups (ie, low-risk vs high-risk mild-to-moderate).ResultsA total of 13 110 individuals from the cross-sectional COGA cohort (mean [SD] age, 37.8 [14.2] years) and 2818 individuals from the longitudinal COGA cohort (mean baseline [SD] age, 16.1 [3.2] years) were included. Associations with alcohol-related, psychiatric, EEG, and AUD polygenic score measures reinforced the role of increasing criterion counts as indexing severity. Yet within mild-to-moderate AUD (2-5 criteria), the presence of specific high-risk criteria (eg, withdrawal) identified a group reporting heavier drinking and greater psychiatric comorbidity even after accounting for criterion count differences. In longitudinal analyses, prior mild-to-moderate AUD characterized by endorsement of at leas
Published: 2023

6. Genome-wide admixture mapping of DSM-IV alcohol dependence, criterion count, and the self-rating of the effects of ethanol in African American populations.

Author: Lai, Dongbing, Lai, Dongbing, Kapoor, Manav, Wetherill, Leah, Schwandt, Melanie, Ramchandani, Vijay A, Goldman, David, Chao, Michael, Almasy, Laura, Bucholz, Kathleen, Hart, Ronald P, Kamarajan, Chella, Meyers, Jacquelyn L, Nurnberger, John I, Tischfield, Jay, Edenberg, Howard J, Schuckit, Marc, Goate, Alison, Scott, Denise M, Porjesz, Bernice, Agrawal, Arpana, Foroud, Tatiana, Lai, Dongbing, Lai, Dongbing, Kapoor, Manav, Wetherill, Leah, Schwandt, Melanie, Ramchandani, Vijay A, Goldman, David, Chao, Michael, Almasy, Laura, Bucholz, Kathleen, Hart, Ronald P, Kamarajan, Chella, Meyers, Jacquelyn L, Nurnberger, John I, Tischfield, Jay, Edenberg, Howard J, Schuckit, Marc, Goate, Alison, Scott, Denise M, Porjesz, Bernice, Agrawal, Arpana, and Foroud, Tatiana
Abstract: African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response to alcohol than European Americans. Genome-wide association studies (GWAS) have identified genes/variants associated with alcohol dependence specifically in AA; however, the sample sizes are still not large enough to detect variants with small effects. Admixture mapping is an alternative way to identify alcohol dependence genes/variants that may be unique to AA. In this study, we performed the first admixture mapping of DSM-IV alcohol dependence diagnosis, DSM-IV alcohol dependence criterion count, and two scores from the self-rating of effects of ethanol (SRE) as measures of response to alcohol: the first five times of using alcohol (SRE-5) and average of SRE across three times (SRE-T). Findings revealed a region on chromosome 4 that was genome-wide significant for SRE-5 (p value = 4.18E-05). Fine mapping did not identify a single causal variant to be associated with SRE-5; instead, conditional analysis concluded that multiple variants collectively explained the admixture mapping signal. PPARGC1A, a gene that has been linked to alcohol consumption in previous studies, is located in this region. Our finding suggests that admixture mapping is a useful tool to identify genes/variants that may have been missed by current GWAS approaches in admixed populations.
Published: 2021

7. Genome-wide admixture mapping of DSM-IV alcohol dependence, criterion count, and the self-rating of the effects of ethanol in African American populations.

Author: Lai, Dongbing, Lai, Dongbing, Kapoor, Manav, Wetherill, Leah, Schwandt, Melanie, Ramchandani, Vijay A, Goldman, David, Chao, Michael, Almasy, Laura, Bucholz, Kathleen, Hart, Ronald P, Kamarajan, Chella, Meyers, Jacquelyn L, Nurnberger, John I, Tischfield, Jay, Edenberg, Howard J, Schuckit, Marc, Goate, Alison, Scott, Denise M, Porjesz, Bernice, Agrawal, Arpana, Foroud, Tatiana, Lai, Dongbing, Lai, Dongbing, Kapoor, Manav, Wetherill, Leah, Schwandt, Melanie, Ramchandani, Vijay A, Goldman, David, Chao, Michael, Almasy, Laura, Bucholz, Kathleen, Hart, Ronald P, Kamarajan, Chella, Meyers, Jacquelyn L, Nurnberger, John I, Tischfield, Jay, Edenberg, Howard J, Schuckit, Marc, Goate, Alison, Scott, Denise M, Porjesz, Bernice, Agrawal, Arpana, and Foroud, Tatiana
Abstract: African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response to alcohol than European Americans. Genome-wide association studies (GWAS) have identified genes/variants associated with alcohol dependence specifically in AA; however, the sample sizes are still not large enough to detect variants with small effects. Admixture mapping is an alternative way to identify alcohol dependence genes/variants that may be unique to AA. In this study, we performed the first admixture mapping of DSM-IV alcohol dependence diagnosis, DSM-IV alcohol dependence criterion count, and two scores from the self-rating of effects of ethanol (SRE) as measures of response to alcohol: the first five times of using alcohol (SRE-5) and average of SRE across three times (SRE-T). Findings revealed a region on chromosome 4 that was genome-wide significant for SRE-5 (p value = 4.18E-05). Fine mapping did not identify a single causal variant to be associated with SRE-5; instead, conditional analysis concluded that multiple variants collectively explained the admixture mapping signal. PPARGC1A, a gene that has been linked to alcohol consumption in previous studies, is located in this region. Our finding suggests that admixture mapping is a useful tool to identify genes/variants that may have been missed by current GWAS approaches in admixed populations.
Published: 2021

8. Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

Author: Lai, Dongbing, Lai, Dongbing, Alipanahi, Babak, Fontanillas, Pierre, Schwantes-An, Tae-Hwi, Aasly, Jan, Alcalay, Roy N, Beecham, Gary W, Berg, Daniela, Bressman, Susan, Brice, Alexis, Brockman, Kathrin, Clark, Lorraine, Cookson, Mark, Das, Sayantan, Van Deerlin, Vivianna, Follett, Jordan, Farrer, Matthew J, Trinh, Joanne, Gasser, Thomas, Goldwurm, Stefano, Gustavsson, Emil, Klein, Christine, Lang, Anthony E, Langston, J William, Latourelle, Jeanne, Lynch, Timothy, Marder, Karen, Marras, Connie, Martin, Eden R, McLean, Cory Y, Mejia-Santana, Helen, Molho, Eric, Myers, Richard H, Nuytemans, Karen, Ozelius, Laurie, Payami, Haydeh, Raymond, Deborah, Rogaeva, Ekaterina, Rogers, Michael P, Ross, Owen A, Samii, Ali, Saunders-Pullman, Rachel, Schüle, Birgitt, Schulte, Claudia, Scott, William K, Tanner, Caroline, Tolosa, Eduardo, Tomkins, James E, Vilas, Dolores, Trojanowski, John Q, 23andMe Research Team, Uitti, Ryan, Vance, Jeffery M, Visanji, Naomi P, Wszolek, Zbigniew K, Zabetian, Cyrus P, Mirelman, Anat, Giladi, Nir, Orr Urtreger, Avi, Cannon, Paul, Fiske, Brian, Foroud, Tatiana, Lai, Dongbing, Lai, Dongbing, Alipanahi, Babak, Fontanillas, Pierre, Schwantes-An, Tae-Hwi, Aasly, Jan, Alcalay, Roy N, Beecham, Gary W, Berg, Daniela, Bressman, Susan, Brice, Alexis, Brockman, Kathrin, Clark, Lorraine, Cookson, Mark, Das, Sayantan, Van Deerlin, Vivianna, Follett, Jordan, Farrer, Matthew J, Trinh, Joanne, Gasser, Thomas, Goldwurm, Stefano, Gustavsson, Emil, Klein, Christine, Lang, Anthony E, Langston, J William, Latourelle, Jeanne, Lynch, Timothy, Marder, Karen, Marras, Connie, Martin, Eden R, McLean, Cory Y, Mejia-Santana, Helen, Molho, Eric, Myers, Richard H, Nuytemans, Karen, Ozelius, Laurie, Payami, Haydeh, Raymond, Deborah, Rogaeva, Ekaterina, Rogers, Michael P, Ross, Owen A, Samii, Ali, Saunders-Pullman, Rachel, Schüle, Birgitt, Schulte, Claudia, Scott, William K, Tanner, Caroline, Tolosa, Eduardo, Tomkins, James E, Vilas, Dolores, Trojanowski, John Q, 23andMe Research Team, Uitti, Ryan, Vance, Jeffery M, Visanji, Naomi P, Wszolek, Zbigniew K, Zabetian, Cyrus P, Mirelman, Anat, Giladi, Nir, Orr Urtreger, Avi, Cannon, Paul, Fiske, Brian, and Foroud, Tatiana
Abstract: ObjectiveThe aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.MethodsWe performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.ResultsA variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.InterpretationThis study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.
Published: 2021

9. Genome-wide association studies of the self-rating of effects of ethanol (SRE).

Author: Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Kapoor, Manav, Johnson, Emma C, Schwandt, Melanie, Ramchandani, Vijay A, Goldman, David, Joslyn, Geoff, Rao, Xi, Liu, Yunlong, Farris, Sean, Mayfield, R Dayne, Dick, Danielle, Hesselbrock, Victor, Kramer, John, McCutcheon, Vivia V, Nurnberger, John, Tischfield, Jay, Goate, Alison, Edenberg, Howard J, Porjesz, Bernice, Agrawal, Arpana, Foroud, Tatiana, Schuckit, Marc, Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Kapoor, Manav, Johnson, Emma C, Schwandt, Melanie, Ramchandani, Vijay A, Goldman, David, Joslyn, Geoff, Rao, Xi, Liu, Yunlong, Farris, Sean, Mayfield, R Dayne, Dick, Danielle, Hesselbrock, Victor, Kramer, John, McCutcheon, Vivia V, Nurnberger, John, Tischfield, Jay, Goate, Alison, Edenberg, Howard J, Porjesz, Bernice, Agrawal, Arpana, Foroud, Tatiana, and Schuckit, Marc
Abstract: The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders.
Published: 2020

10. Genome-wide association studies of the self-rating of effects of ethanol (SRE).

Author: Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Kapoor, Manav, Johnson, Emma C, Schwandt, Melanie, Ramchandani, Vijay A, Goldman, David, Joslyn, Geoff, Rao, Xi, Liu, Yunlong, Farris, Sean, Mayfield, R Dayne, Dick, Danielle, Hesselbrock, Victor, Kramer, John, McCutcheon, Vivia V, Nurnberger, John, Tischfield, Jay, Goate, Alison, Edenberg, Howard J, Porjesz, Bernice, Agrawal, Arpana, Foroud, Tatiana, Schuckit, Marc, Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Kapoor, Manav, Johnson, Emma C, Schwandt, Melanie, Ramchandani, Vijay A, Goldman, David, Joslyn, Geoff, Rao, Xi, Liu, Yunlong, Farris, Sean, Mayfield, R Dayne, Dick, Danielle, Hesselbrock, Victor, Kramer, John, McCutcheon, Vivia V, Nurnberger, John, Tischfield, Jay, Goate, Alison, Edenberg, Howard J, Porjesz, Bernice, Agrawal, Arpana, Foroud, Tatiana, and Schuckit, Marc
Abstract: The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders.
Published: 2020

11. Genome-wide association studies of the self-rating of effects of ethanol (SRE).

Author: Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Kapoor, Manav, Johnson, Emma, Schwandt, Melanie, Ramchandani, Vijay, Goldman, David, Joslyn, Geoff, Rao, Xi, Liu, Yunlong, Farris, Sean, Mayfield, R, Dick, Danielle, Hesselbrock, Victor, Kramer, John, McCutcheon, Vivia, Nurnberger, John, Tischfield, Jay, Goate, Alison, Edenberg, Howard, Porjesz, Bernice, Agrawal, Arpana, Foroud, Tatiana, Schuckit, Marc, Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Kapoor, Manav, Johnson, Emma, Schwandt, Melanie, Ramchandani, Vijay, Goldman, David, Joslyn, Geoff, Rao, Xi, Liu, Yunlong, Farris, Sean, Mayfield, R, Dick, Danielle, Hesselbrock, Victor, Kramer, John, McCutcheon, Vivia, Nurnberger, John, Tischfield, Jay, Goate, Alison, Edenberg, Howard, Porjesz, Bernice, Agrawal, Arpana, Foroud, Tatiana, and Schuckit, Marc
Abstract: The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders.
Published: 2020

12. Intracranial aneurysm classifier using phenotypic factors : an international pooled analysis

Author: Morel, Sandrine, Hostettler, Isabel C., Spinner, Georg R., Bourcier, Romain, Pera, Joanna, Meling, Torstein, Alg, Varinder, Houlden, Henry, Bakker, Mark, van’t Hof, Femke, Rinkel, Gabriel, Foroud, Tatiana, Lai, Dongbing, Moomaw, Charles, Worrall, Bradford, Caroff, Jildaz, Constant-dits-Beaufils, Pacôme, Karakachoff, Matilde, Rimbert, Antoine, Rouchaud, Aymeric, Gaal-Paavola, Emilia, Kaukovalta, Hanna, Kivisaari, Riku, Laakso, Aki, Jahromi, Behnam, Tulamo, Riikka, Friedrich, Christoph, Dauvillier, Jerome, Hirsch, Sven, Isidor, Nathalie, Kulcsàr, Zolt, Lövblad, Karl, Martin, Olivier, Machi, Paolo, Mendes Pereira, Vitor, Rüfenacht, Daniel, Schaller, Karl, Schilling, Sabine, Slowik, Agnieszka, Jaaskelainen, Juha, von und zu Fraunberg, Mikael, Jiménez-Conde, Jordi, Cuadrado-Godia, Elisa, Soriano-Tárraga, Carolina, Millwood, Iona, Walters, Robin, The @neurIST project, The ICAN Study Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study Investigators, International Stroke Genetics Consortium (ISGC), Kim, Helen, Redon, Richard, Ko, Nerissa, Rouleau, Guy, Lindgren, Antti, Niemelä, Mika, Desal, Hubert, Woo, Daniel, Broderick, Joseph, Werring, David, Ruigrok, Ynte, Bijlenga, Philippe, Morel, Sandrine, Hostettler, Isabel C., Spinner, Georg R., Bourcier, Romain, Pera, Joanna, Meling, Torstein, Alg, Varinder, Houlden, Henry, Bakker, Mark, van’t Hof, Femke, Rinkel, Gabriel, Foroud, Tatiana, Lai, Dongbing, Moomaw, Charles, Worrall, Bradford, Caroff, Jildaz, Constant-dits-Beaufils, Pacôme, Karakachoff, Matilde, Rimbert, Antoine, Rouchaud, Aymeric, Gaal-Paavola, Emilia, Kaukovalta, Hanna, Kivisaari, Riku, Laakso, Aki, Jahromi, Behnam, Tulamo, Riikka, Friedrich, Christoph, Dauvillier, Jerome, Hirsch, Sven, Isidor, Nathalie, Kulcsàr, Zolt, Lövblad, Karl, Martin, Olivier, Machi, Paolo, Mendes Pereira, Vitor, Rüfenacht, Daniel, Schaller, Karl, Schilling, Sabine, Slowik, Agnieszka, Jaaskelainen, Juha, von und zu Fraunberg, Mikael, Jiménez-Conde, Jordi, Cuadrado-Godia, Elisa, Soriano-Tárraga, Carolina, Millwood, Iona, Walters, Robin, The @neurIST project, The ICAN Study Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study Investigators, International Stroke Genetics Consortium (ISGC), Kim, Helen, Redon, Richard, Ko, Nerissa, Rouleau, Guy, Lindgren, Antti, Niemelä, Mika, Desal, Hubert, Woo, Daniel, Broderick, Joseph, Werring, David, Ruigrok, Ynte, and Bijlenga, Philippe
Abstract: Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making.
Published: 2022

13. Item-Level Genome-Wide Association Study of the Alcohol Use Disorders Identification Test in Three Population-Based Cohorts

Author: Mallard, Travis T., Savage, Jeanne E., Johnson, Emma C., Huang, Yuye, Edwards, Alexis C., Hottenga, Jouke J., Grotzinger, Andrew D., Gustavson, Daniel E., Jennings, Mariela V., Anokhin, Andrey, Dick, Danielle M., Edenberg, Howard J., Kramer, John R., Lai, Dongbing, Meyers, Jacquelyn L., Pandey, Ashwini K., Harden, Kathryn Paige, Nivard, Michel G., de Geus, Eco J.C., Boomsma, Dorret I., Agrawal, Arpana, Davis, Lea K., Clarke, Toni Kim, Palmer, Abraham A., Sanchez-Roige, Sandra, Mallard, Travis T., Savage, Jeanne E., Johnson, Emma C., Huang, Yuye, Edwards, Alexis C., Hottenga, Jouke J., Grotzinger, Andrew D., Gustavson, Daniel E., Jennings, Mariela V., Anokhin, Andrey, Dick, Danielle M., Edenberg, Howard J., Kramer, John R., Lai, Dongbing, Meyers, Jacquelyn L., Pandey, Ashwini K., Harden, Kathryn Paige, Nivard, Michel G., de Geus, Eco J.C., Boomsma, Dorret I., Agrawal, Arpana, Davis, Lea K., Clarke, Toni Kim, Palmer, Abraham A., and Sanchez-Roige, Sandra
Abstract: OBJECTIVE: Genome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT. METHODS: To explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases. RESULTS: The authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ("consumption" and "problems," rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health. CONCLUSIONS: This work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more clo
Published: 2022
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14. High Polygenic Risk Scores Are Associated With Early Age of Onset of Alcohol Use Disorder in Adolescents and Young Adults at Risk.

Author: Nurnberger, John I, Nurnberger, John I, Wang, Yumin, Zang, Yong, Lai, Dongbing, Wetherill, Leah, Edenberg, Howard J, Aliev, Fazil, Plawecki, Martin H, Chorlian, David, Chan, Grace, Bucholz, Kathleen, Bauer, Lance, Kamarajan, Chella, Salvatore, Jessica E, Kapoor, Manav, Hesselbrock, Victor, Dick, Danielle, Bierut, Laura, McCutcheon, Vivia, Meyers, Jacquelyn L, Porjesz, Bernice, Kramer, John, Kuperman, Samuel, Kinreich, Sivan, Anokhin, Andrey P, Collaborative Study on the Genetics of Alcoholism, Nurnberger, John I, Nurnberger, John I, Wang, Yumin, Zang, Yong, Lai, Dongbing, Wetherill, Leah, Edenberg, Howard J, Aliev, Fazil, Plawecki, Martin H, Chorlian, David, Chan, Grace, Bucholz, Kathleen, Bauer, Lance, Kamarajan, Chella, Salvatore, Jessica E, Kapoor, Manav, Hesselbrock, Victor, Dick, Danielle, Bierut, Laura, McCutcheon, Vivia, Meyers, Jacquelyn L, Porjesz, Bernice, Kramer, John, Kuperman, Samuel, Kinreich, Sivan, Anokhin, Andrey P, and Collaborative Study on the Genetics of Alcoholism
Abstract: BackgroundGenome-wide association studies have been conducted in alcohol use disorder (AUD), and they permit the use of polygenic risk scores (PRSs), in combination with clinical variables, to predict the onset of AUD in vulnerable populations.MethodsA total of 2794 adolescent/young adult subjects from the Collaborative Study on the Genetics of Alcoholism were followed, with clinical assessments every 2 years. Subjects were genotyped using a genome-wide chip. Separate PRS analyses were performed for subjects of European ancestry and African ancestry. Age of onset of DSM-5 AUD was evaluated using the Cox proportional hazard model. Predictive power was assessed using receiver operating characteristic curves and by analysis of the distribution of PRS.ResultsEuropean ancestry subjects with higher than median PRSs were at greater risk for onset of AUD than subjects with lower than median PRSs (p = 3 × 10-7). Area under the curve for the receiver operating characteristic analysis peaked at 0.88 to 0.95 using PRS plus sex, family history, comorbid disorders, age at first drink, and peer drinking; predictive power was primarily driven by clinical variables. In this high-risk sample, European ancestry subjects with a PRS score in the highest quartile showed a 72% risk for developing AUD and a 35% risk of developing severe AUD (compared with risks of 54% and 16%, respectively, in the lowest quartile).ConclusionsPredictive power for PRSs in the extremes of the distribution suggests that these may have future clinical utility. Uncertainties in interpretation at the individual level still preclude current application.
Published: 2022

15. Alcohol Use Disorder, Psychiatric Comorbidities, Marriage and Divorce in a High-Risk Sample

Author: Thomas, Nathaniel S, Thomas, Nathaniel S, Kuo, Sally I-Chun, Aliev, Fazil, McCutcheon, Vivia V, Meyers, Jacquelyn M, Chan, Grace, Hesselbrock, Victor, Kamarajan, Chella, Kinreich, Sivan, Kramer, John R, Kuperman, Samuel, Lai, Dongbing, Plawecki, Martin H, Porjesz, Bernice, Schuckit, Marc A, Dick, Danielle M, Bucholz, Kathleen K, Salvatore, Jessica E, Thomas, Nathaniel S, Thomas, Nathaniel S, Kuo, Sally I-Chun, Aliev, Fazil, McCutcheon, Vivia V, Meyers, Jacquelyn M, Chan, Grace, Hesselbrock, Victor, Kamarajan, Chella, Kinreich, Sivan, Kramer, John R, Kuperman, Samuel, Lai, Dongbing, Plawecki, Martin H, Porjesz, Bernice, Schuckit, Marc A, Dick, Danielle M, Bucholz, Kathleen K, and Salvatore, Jessica E
Abstract: ObjectiveTo examine associations between alcohol use disorder (AUD), its psychiatric comorbidities, and their interactions, with marital outcomes in a diverse high-risk, genetically informative sample.MethodParticipants included European ancestry (EA; n = 4,045) and African ancestry (AA; n = 1,550) individuals from the multigenerational Collaborative Study on the Genetics of Alcoholism (COGA) sample (56% female, Mage ∼ 41 years). Outcomes were lifetime marriage and divorce. Predictors included lifetime AUD, an alcohol problems polygenic score (PRS), and AUD comorbidities, including conduct or antisocial personality disorder (ASP), cannabis dependence/abuse (CAN), frequent tobacco use (TOB), and major depressive disorder (MDD). Mixed effect Cox models and generalized linear mixed effects models were fit.ResultsAmong EA participants, those with AUD and CAN were less likely to marry (hazard ratios [HRs] 0.70-0.83, ps < 0.01). Among AA participants, those with AUD and TOB were less likely to marry (HRs 0.66-0.82, ps < 0.05) and those with MDD were more likely to marry (HR = 1.34, ps < 0.01). Among EA participants, AUD, CAN, TOB, and MDD were associated with higher odds of divorce (odds ratios [ORs] 1.59-2.21, ps < 0.01). Among AA participants, no predictors were significantly associated with divorce. Significant random effects indicated genetic and environmental influences on marriage, but only environmental factors on divorce.ConclusionsIn a high-risk sample, AUD was associated with reduced likelihood of marriage in EA and AA individuals and increased risk of divorce in EA individuals. These associations were largely independent of comorbidities. Genetic and environmental background factors contributed to marriage, while only environmental background factors contributed to divorce. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Published: 2022

16. Item-Level Genome-Wide Association Study of the Alcohol Use Disorders Identification Test in Three Population-Based Cohorts.

Author: Mallard, Travis T, Mallard, Travis T, Savage, Jeanne E, Johnson, Emma C, Huang, Yuye, Edwards, Alexis C, Hottenga, Jouke J, Grotzinger, Andrew D, Gustavson, Daniel E, Jennings, Mariela V, Anokhin, Andrey, Dick, Danielle M, Edenberg, Howard J, Kramer, John R, Lai, Dongbing, Meyers, Jacquelyn L, Pandey, Ashwini K, Harden, Kathryn Paige, Nivard, Michel G, de Geus, Eco JC, Boomsma, Dorret I, Agrawal, Arpana, Davis, Lea K, Clarke, Toni-Kim, Palmer, Abraham A, Sanchez-Roige, Sandra, Mallard, Travis T, Mallard, Travis T, Savage, Jeanne E, Johnson, Emma C, Huang, Yuye, Edwards, Alexis C, Hottenga, Jouke J, Grotzinger, Andrew D, Gustavson, Daniel E, Jennings, Mariela V, Anokhin, Andrey, Dick, Danielle M, Edenberg, Howard J, Kramer, John R, Lai, Dongbing, Meyers, Jacquelyn L, Pandey, Ashwini K, Harden, Kathryn Paige, Nivard, Michel G, de Geus, Eco JC, Boomsma, Dorret I, Agrawal, Arpana, Davis, Lea K, Clarke, Toni-Kim, Palmer, Abraham A, and Sanchez-Roige, Sandra
Abstract: ObjectiveGenome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT.MethodsTo explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases.ResultsThe authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ("consumption" and "problems," rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health.ConclusionsThis work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related t
Published: 2022

17. Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis

Author: Morel, Sandrine, Hostettler, Isabelle, Spinner, Georg, Bourcier, Romain, Pera, Joanna, Meling, Torsten R, Alg, Varinder S, Houlden, H., Bakker, M. K, Van't Hof, Femke, Rinkel, Gabriel J E, Foroud, Tatiana, Lai, Dongbing, Moomaw, Charles J, Worrall, Bradford B, Caroff, Jildaz, Constant-Dits-Beaufils, Pacôme, Karakachoff, Matilde, Cuadrado-Godia, Elisa, Dauvillier, Jerome, Desal, Hubert, Friedrich, Christoph M, Gaal-Paavola, Emilia I, Hirsch, Sven, Ican Study Group, The, Isidor, Nathalie, Jaaskelainen, Juha E, Jahromi, Behnam Rezai, Jiménez-Conde, Jordi, Kaukovalta, Hanna, Kim, Helen, Kivisaari, Riku, Ko, Nerissa U, Kulcsàr, Zolt, Laakso, Aki, Lövblad, Karl O, Lindgren, Antti, Machi, Paolo, Martin, Olivier, Mendes Pereira, Vitor, Millwood, Iona Y, Niemelä, Mika, Rüfenacht, Daniel, Redon, Richard, Rimbert, Antoine, Rouchaud, Aymeric, Schilling, Sabine, Slowik, Agnieszka, Soriano-Tárraga, Carolina, von Und Zu Fraunberg, Mikael, Walters, Robin G, Woo, Daniel, Broderick, Joseph P, Werring, David J, Ruigrok, Ynte M, Bijlenga, Philippe, Morel, Sandrine, Hostettler, Isabelle, Spinner, Georg, Bourcier, Romain, Pera, Joanna, Meling, Torsten R, Alg, Varinder S, Houlden, H., Bakker, M. K, Van't Hof, Femke, Rinkel, Gabriel J E, Foroud, Tatiana, Lai, Dongbing, Moomaw, Charles J, Worrall, Bradford B, Caroff, Jildaz, Constant-Dits-Beaufils, Pacôme, Karakachoff, Matilde, Cuadrado-Godia, Elisa, Dauvillier, Jerome, Desal, Hubert, Friedrich, Christoph M, Gaal-Paavola, Emilia I, Hirsch, Sven, Ican Study Group, The, Isidor, Nathalie, Jaaskelainen, Juha E, Jahromi, Behnam Rezai, Jiménez-Conde, Jordi, Kaukovalta, Hanna, Kim, Helen, Kivisaari, Riku, Ko, Nerissa U, Kulcsàr, Zolt, Laakso, Aki, Lövblad, Karl O, Lindgren, Antti, Machi, Paolo, Martin, Olivier, Mendes Pereira, Vitor, Millwood, Iona Y, Niemelä, Mika, Rüfenacht, Daniel, Redon, Richard, Rimbert, Antoine, Rouchaud, Aymeric, Schilling, Sabine, Slowik, Agnieszka, Soriano-Tárraga, Carolina, von Und Zu Fraunberg, Mikael, Walters, Robin G, Woo, Daniel, Broderick, Joseph P, Werring, David J, Ruigrok, Ynte M, and Bijlenga, Philippe
Abstract: Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making., + ID der Publikation: hslu_97752 + Art des Beitrages: Wissenschaftliche Medien + Jahrgang: 12 + Sprache: Englisch + Letzte Aktualisierung: 2023-07-10 16:04:23
Published: 2022

18. Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis

Author: Morel, Sandrine, Hostettler, Isabelle, Spinner, Georg, Bourcier, Romain, Pera, Joanna, Meling, Torsten R, Alg, Varinder S, Houlden, H., Bakker, M. K, Van't Hof, Femke, Rinkel, Gabriel J E, Foroud, Tatiana, Lai, Dongbing, Moomaw, Charles J, Worrall, Bradford B, Caroff, Jildaz, Constant-Dits-Beaufils, Pacôme, Karakachoff, Matilde, Cuadrado-Godia, Elisa, Dauvillier, Jerome, Desal, Hubert, Friedrich, Christoph M, Gaal-Paavola, Emilia I, Hirsch, Sven, Ican Study Group, The, Isidor, Nathalie, Jaaskelainen, Juha E, Jahromi, Behnam Rezai, Jiménez-Conde, Jordi, Kaukovalta, Hanna, Kim, Helen, Kivisaari, Riku, Ko, Nerissa U, Kulcsàr, Zolt, Laakso, Aki, Lövblad, Karl O, Lindgren, Antti, Machi, Paolo, Martin, Olivier, Mendes Pereira, Vitor, Millwood, Iona Y, Niemelä, Mika, Rüfenacht, Daniel, Redon, Richard, Rimbert, Antoine, Rouchaud, Aymeric, Schilling, Sabine, Slowik, Agnieszka, Soriano-Tárraga, Carolina, von Und Zu Fraunberg, Mikael, Walters, Robin G, Woo, Daniel, Broderick, Joseph P, Werring, David J, Ruigrok, Ynte M, Bijlenga, Philippe, Morel, Sandrine, Hostettler, Isabelle, Spinner, Georg, Bourcier, Romain, Pera, Joanna, Meling, Torsten R, Alg, Varinder S, Houlden, H., Bakker, M. K, Van't Hof, Femke, Rinkel, Gabriel J E, Foroud, Tatiana, Lai, Dongbing, Moomaw, Charles J, Worrall, Bradford B, Caroff, Jildaz, Constant-Dits-Beaufils, Pacôme, Karakachoff, Matilde, Cuadrado-Godia, Elisa, Dauvillier, Jerome, Desal, Hubert, Friedrich, Christoph M, Gaal-Paavola, Emilia I, Hirsch, Sven, Ican Study Group, The, Isidor, Nathalie, Jaaskelainen, Juha E, Jahromi, Behnam Rezai, Jiménez-Conde, Jordi, Kaukovalta, Hanna, Kim, Helen, Kivisaari, Riku, Ko, Nerissa U, Kulcsàr, Zolt, Laakso, Aki, Lövblad, Karl O, Lindgren, Antti, Machi, Paolo, Martin, Olivier, Mendes Pereira, Vitor, Millwood, Iona Y, Niemelä, Mika, Rüfenacht, Daniel, Redon, Richard, Rimbert, Antoine, Rouchaud, Aymeric, Schilling, Sabine, Slowik, Agnieszka, Soriano-Tárraga, Carolina, von Und Zu Fraunberg, Mikael, Walters, Robin G, Woo, Daniel, Broderick, Joseph P, Werring, David J, Ruigrok, Ynte M, and Bijlenga, Philippe
Abstract: Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making., + ID der Publikation: hslu_97752 + Art des Beitrages: Wissenschaftliche Medien + Jahrgang: 12 + Sprache: Englisch + Letzte Aktualisierung: 2023-07-10 16:04:23
Published: 2022

19. Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis

Author: Morel, Sandrine, Hostettler, Isabelle, Spinner, Georg, Bourcier, Romain, Pera, Joanna, Meling, Torsten R, Alg, Varinder S, Houlden, H., Bakker, M. K, Van't Hof, Femke, Rinkel, Gabriel J E, Foroud, Tatiana, Lai, Dongbing, Moomaw, Charles J, Worrall, Bradford B, Caroff, Jildaz, Constant-Dits-Beaufils, Pacôme, Karakachoff, Matilde, Cuadrado-Godia, Elisa, Dauvillier, Jerome, Desal, Hubert, Friedrich, Christoph M, Gaal-Paavola, Emilia I, Hirsch, Sven, Ican Study Group, The, Isidor, Nathalie, Jaaskelainen, Juha E, Jahromi, Behnam Rezai, Jiménez-Conde, Jordi, Kaukovalta, Hanna, Kim, Helen, Kivisaari, Riku, Ko, Nerissa U, Kulcsàr, Zolt, Laakso, Aki, Lövblad, Karl O, Lindgren, Antti, Machi, Paolo, Martin, Olivier, Mendes Pereira, Vitor, Millwood, Iona Y, Niemelä, Mika, Rüfenacht, Daniel, Redon, Richard, Rimbert, Antoine, Rouchaud, Aymeric, Schilling, Sabine, Slowik, Agnieszka, Soriano-Tárraga, Carolina, von Und Zu Fraunberg, Mikael, Walters, Robin G, Woo, Daniel, Broderick, Joseph P, Werring, David J, Ruigrok, Ynte M, Bijlenga, Philippe, Morel, Sandrine, Hostettler, Isabelle, Spinner, Georg, Bourcier, Romain, Pera, Joanna, Meling, Torsten R, Alg, Varinder S, Houlden, H., Bakker, M. K, Van't Hof, Femke, Rinkel, Gabriel J E, Foroud, Tatiana, Lai, Dongbing, Moomaw, Charles J, Worrall, Bradford B, Caroff, Jildaz, Constant-Dits-Beaufils, Pacôme, Karakachoff, Matilde, Cuadrado-Godia, Elisa, Dauvillier, Jerome, Desal, Hubert, Friedrich, Christoph M, Gaal-Paavola, Emilia I, Hirsch, Sven, Ican Study Group, The, Isidor, Nathalie, Jaaskelainen, Juha E, Jahromi, Behnam Rezai, Jiménez-Conde, Jordi, Kaukovalta, Hanna, Kim, Helen, Kivisaari, Riku, Ko, Nerissa U, Kulcsàr, Zolt, Laakso, Aki, Lövblad, Karl O, Lindgren, Antti, Machi, Paolo, Martin, Olivier, Mendes Pereira, Vitor, Millwood, Iona Y, Niemelä, Mika, Rüfenacht, Daniel, Redon, Richard, Rimbert, Antoine, Rouchaud, Aymeric, Schilling, Sabine, Slowik, Agnieszka, Soriano-Tárraga, Carolina, von Und Zu Fraunberg, Mikael, Walters, Robin G, Woo, Daniel, Broderick, Joseph P, Werring, David J, Ruigrok, Ynte M, and Bijlenga, Philippe
Abstract: Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making., + ID der Publikation: hslu_97752 + Art des Beitrages: Wissenschaftliche Medien + Jahrgang: 12 + Sprache: Englisch + Letzte Aktualisierung: 2023-07-10 16:04:23
Published: 2022

20. Item-Level Genome-Wide Association Study of the Alcohol Use Disorders Identification Test in Three Population-Based Cohorts

Author: Mallard, Travis T., Savage, Jeanne E., Johnson, Emma C., Huang, Yuye, Edwards, Alexis C., Hottenga, Jouke J., Grotzinger, Andrew D., Gustavson, Daniel E., Jennings, Mariela V., Anokhin, Andrey, Dick, Danielle M., Edenberg, Howard J., Kramer, John R., Lai, Dongbing, Meyers, Jacquelyn L., Pandey, Ashwini K., Harden, Kathryn Paige, Nivard, Michel G., de Geus, Eco J.C., Boomsma, Dorret I., Agrawal, Arpana, Davis, Lea K., Clarke, Toni Kim, Palmer, Abraham A., Sanchez-Roige, Sandra, Mallard, Travis T., Savage, Jeanne E., Johnson, Emma C., Huang, Yuye, Edwards, Alexis C., Hottenga, Jouke J., Grotzinger, Andrew D., Gustavson, Daniel E., Jennings, Mariela V., Anokhin, Andrey, Dick, Danielle M., Edenberg, Howard J., Kramer, John R., Lai, Dongbing, Meyers, Jacquelyn L., Pandey, Ashwini K., Harden, Kathryn Paige, Nivard, Michel G., de Geus, Eco J.C., Boomsma, Dorret I., Agrawal, Arpana, Davis, Lea K., Clarke, Toni Kim, Palmer, Abraham A., and Sanchez-Roige, Sandra
Abstract: OBJECTIVE: Genome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT. METHODS: To explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases. RESULTS: The authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ("consumption" and "problems," rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health. CONCLUSIONS: This work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more clo
Published: 2022
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21. Intracranial aneurysm classifier using phenotypic factors : an international pooled analysis

Author: Morel, Sandrine, Hostettler, Isabel C., Spinner, Georg R., Bourcier, Romain, Pera, Joanna, Meling, Torstein, Alg, Varinder, Houlden, Henry, Bakker, Mark, van’t Hof, Femke, Rinkel, Gabriel, Foroud, Tatiana, Lai, Dongbing, Moomaw, Charles, Worrall, Bradford, Caroff, Jildaz, Constant-dits-Beaufils, Pacôme, Karakachoff, Matilde, Rimbert, Antoine, Rouchaud, Aymeric, Gaal-Paavola, Emilia, Kaukovalta, Hanna, Kivisaari, Riku, Laakso, Aki, Jahromi, Behnam, Tulamo, Riikka, Friedrich, Christoph, Dauvillier, Jerome, Hirsch, Sven, Isidor, Nathalie, Kulcsàr, Zolt, Lövblad, Karl, Martin, Olivier, Machi, Paolo, Mendes Pereira, Vitor, Rüfenacht, Daniel, Schaller, Karl, Schilling, Sabine, Slowik, Agnieszka, Jaaskelainen, Juha, von und zu Fraunberg, Mikael, Jiménez-Conde, Jordi, Cuadrado-Godia, Elisa, Soriano-Tárraga, Carolina, Millwood, Iona, Walters, Robin, The @neurIST project, The ICAN Study Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study Investigators, International Stroke Genetics Consortium (ISGC), Kim, Helen, Redon, Richard, Ko, Nerissa, Rouleau, Guy, Lindgren, Antti, Niemelä, Mika, Desal, Hubert, Woo, Daniel, Broderick, Joseph, Werring, David, Ruigrok, Ynte, Bijlenga, Philippe, Morel, Sandrine, Hostettler, Isabel C., Spinner, Georg R., Bourcier, Romain, Pera, Joanna, Meling, Torstein, Alg, Varinder, Houlden, Henry, Bakker, Mark, van’t Hof, Femke, Rinkel, Gabriel, Foroud, Tatiana, Lai, Dongbing, Moomaw, Charles, Worrall, Bradford, Caroff, Jildaz, Constant-dits-Beaufils, Pacôme, Karakachoff, Matilde, Rimbert, Antoine, Rouchaud, Aymeric, Gaal-Paavola, Emilia, Kaukovalta, Hanna, Kivisaari, Riku, Laakso, Aki, Jahromi, Behnam, Tulamo, Riikka, Friedrich, Christoph, Dauvillier, Jerome, Hirsch, Sven, Isidor, Nathalie, Kulcsàr, Zolt, Lövblad, Karl, Martin, Olivier, Machi, Paolo, Mendes Pereira, Vitor, Rüfenacht, Daniel, Schaller, Karl, Schilling, Sabine, Slowik, Agnieszka, Jaaskelainen, Juha, von und zu Fraunberg, Mikael, Jiménez-Conde, Jordi, Cuadrado-Godia, Elisa, Soriano-Tárraga, Carolina, Millwood, Iona, Walters, Robin, The @neurIST project, The ICAN Study Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study Investigators, International Stroke Genetics Consortium (ISGC), Kim, Helen, Redon, Richard, Ko, Nerissa, Rouleau, Guy, Lindgren, Antti, Niemelä, Mika, Desal, Hubert, Woo, Daniel, Broderick, Joseph, Werring, David, Ruigrok, Ynte, and Bijlenga, Philippe
Abstract: Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making.
Published: 2022

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

Author: Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Bertelsen, Sarah, Carey, Caitlin E, Kamarajan, Chella, Kapoor, Manav, Meyers, Jacquelyn L, Anokhin, Andrey P, Bennett, David A, Bucholz, Kathleen K, Chang, Katharine K, De Jager, Philip L, Dick, Danielle M, Hesselbrock, Victor, Kramer, John, Kuperman, Samuel, Nurnberger, John I, Raj, Towfique, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Hariri, Ahmad R, Edenberg, Howard J, Agrawal, Arpana, Bogdan, Ryan, Porjesz, Bernice, Goate, Alison M, Foroud, Tatiana, Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Bertelsen, Sarah, Carey, Caitlin E, Kamarajan, Chella, Kapoor, Manav, Meyers, Jacquelyn L, Anokhin, Andrey P, Bennett, David A, Bucholz, Kathleen K, Chang, Katharine K, De Jager, Philip L, Dick, Danielle M, Hesselbrock, Victor, Kramer, John, Kuperman, Samuel, Nurnberger, John I, Raj, Towfique, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Hariri, Ahmad R, Edenberg, Howard J, Agrawal, Arpana, Bogdan, Ryan, Porjesz, Bernice, Goate, Alison M, and Foroud, Tatiana
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.
Published: 2019

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

Author: Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Bertelsen, Sarah, Carey, Caitlin E, Kamarajan, Chella, Kapoor, Manav, Meyers, Jacquelyn L, Anokhin, Andrey P, Bennett, David A, Bucholz, Kathleen K, Chang, Katharine K, De Jager, Philip L, Dick, Danielle M, Hesselbrock, Victor, Kramer, John, Kuperman, Samuel, Nurnberger, John I, Raj, Towfique, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Hariri, Ahmad R, Edenberg, Howard J, Agrawal, Arpana, Bogdan, Ryan, Porjesz, Bernice, Goate, Alison M, Foroud, Tatiana, Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Bertelsen, Sarah, Carey, Caitlin E, Kamarajan, Chella, Kapoor, Manav, Meyers, Jacquelyn L, Anokhin, Andrey P, Bennett, David A, Bucholz, Kathleen K, Chang, Katharine K, De Jager, Philip L, Dick, Danielle M, Hesselbrock, Victor, Kramer, John, Kuperman, Samuel, Nurnberger, John I, Raj, Towfique, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Hariri, Ahmad R, Edenberg, Howard J, Agrawal, Arpana, Bogdan, Ryan, Porjesz, Bernice, Goate, Alison M, and Foroud, Tatiana
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.
Published: 2019

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

Author: Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Bertelsen, Sarah, Carey, Caitlin, Kamarajan, Chella, Kapoor, Manav, Meyers, Jacquelyn, Anokhin, Andrey, Bennett, David, Bucholz, Kathleen, Chang, Katharine, De Jager, Philip, Dick, Danielle, Hesselbrock, Victor, Kramer, John, Kuperman, Samuel, Nurnberger, John, Raj, Towfique, Scott, Denise, Taylor, Robert, Tischfield, Jay, Hariri, Ahmad, Edenberg, Howard, Agrawal, Arpana, Bogdan, Ryan, Porjesz, Bernice, Goate, Alison, Foroud, Tatiana, Schuckit, Marc, Lai, Dongbing, Lai, Dongbing, Wetherill, Leah, Bertelsen, Sarah, Carey, Caitlin, Kamarajan, Chella, Kapoor, Manav, Meyers, Jacquelyn, Anokhin, Andrey, Bennett, David, Bucholz, Kathleen, Chang, Katharine, De Jager, Philip, Dick, Danielle, Hesselbrock, Victor, Kramer, John, Kuperman, Samuel, Nurnberger, John, Raj, Towfique, Scott, Denise, Taylor, Robert, Tischfield, Jay, Hariri, Ahmad, Edenberg, Howard, Agrawal, Arpana, Bogdan, Ryan, Porjesz, Bernice, Goate, Alison, Foroud, Tatiana, and Schuckit, Marc
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.
Published: 2019

25. Integration of evidence across human and model organism studies: A meeting report.

Author: Palmer, Rohan HC, Palmer, Rohan HC, Johnson, Emma C, Won, Hyejung, Polimanti, Renato, Kapoor, Manav, Chitre, Apurva, Bogue, Molly A, Benca-Bachman, Chelsie E, Parker, Clarissa C, Verma, Anurag, Reynolds, Timothy, Ernst, Jason, Bray, Michael, Kwon, Soo Bin, Lai, Dongbing, Quach, Bryan C, Gaddis, Nathan C, Saba, Laura, Chen, Hao, Hawrylycz, Michael, Zhang, Shan, Zhou, Yuan, Mahaffey, Spencer, Fischer, Christian, Sanchez-Roige, Sandra, Bandrowski, Anita, Lu, Qing, Shen, Li, Philip, Vivek, Gelernter, Joel, Bierut, Laura J, Hancock, Dana B, Edenberg, Howard J, Johnson, Eric O, Nestler, Eric J, Barr, Peter B, Prins, Pjotr, Smith, Desmond J, Akbarian, Schahram, Thorgeirsson, Thorgeir, Walton, Dave, Baker, Erich, Jacobson, Daniel, Palmer, Abraham A, Miles, Michael, Chesler, Elissa J, Emerson, Jake, Agrawal, Arpana, Martone, Maryann, Williams, Robert W, Palmer, Rohan HC, Palmer, Rohan HC, Johnson, Emma C, Won, Hyejung, Polimanti, Renato, Kapoor, Manav, Chitre, Apurva, Bogue, Molly A, Benca-Bachman, Chelsie E, Parker, Clarissa C, Verma, Anurag, Reynolds, Timothy, Ernst, Jason, Bray, Michael, Kwon, Soo Bin, Lai, Dongbing, Quach, Bryan C, Gaddis, Nathan C, Saba, Laura, Chen, Hao, Hawrylycz, Michael, Zhang, Shan, Zhou, Yuan, Mahaffey, Spencer, Fischer, Christian, Sanchez-Roige, Sandra, Bandrowski, Anita, Lu, Qing, Shen, Li, Philip, Vivek, Gelernter, Joel, Bierut, Laura J, Hancock, Dana B, Edenberg, Howard J, Johnson, Eric O, Nestler, Eric J, Barr, Peter B, Prins, Pjotr, Smith, Desmond J, Akbarian, Schahram, Thorgeirsson, Thorgeir, Walton, Dave, Baker, Erich, Jacobson, Daniel, Palmer, Abraham A, Miles, Michael, Chesler, Elissa J, Emerson, Jake, Agrawal, Arpana, Martone, Maryann, and Williams, Robert W
Abstract: The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration-particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.
Published: 2021

26. Polygenic contributions to alcohol use and alcohol use disorders across population-based and clinically ascertained samples.

Author: Johnson, Emma C, Johnson, Emma C, Sanchez-Roige, Sandra, Acion, Laura, Adams, Mark J, Bucholz, Kathleen K, Chan, Grace, Chao, Michael J, Chorlian, David B, Dick, Danielle M, Edenberg, Howard J, Foroud, Tatiana, Hayward, Caroline, Heron, Jon, Hesselbrock, Victor, Hickman, Matthew, Kendler, Kenneth S, Kinreich, Sivan, Kramer, John, Kuo, Sally I-Chun, Kuperman, Samuel, Lai, Dongbing, McIntosh, Andrew M, Meyers, Jacquelyn L, Plawecki, Martin H, Porjesz, Bernice, Porteous, David, Schuckit, Marc A, Su, Jinni, Zang, Yong, Palmer, Abraham A, Agrawal, Arpana, Clarke, Toni-Kim, Edwards, Alexis C, Johnson, Emma C, Johnson, Emma C, Sanchez-Roige, Sandra, Acion, Laura, Adams, Mark J, Bucholz, Kathleen K, Chan, Grace, Chao, Michael J, Chorlian, David B, Dick, Danielle M, Edenberg, Howard J, Foroud, Tatiana, Hayward, Caroline, Heron, Jon, Hesselbrock, Victor, Hickman, Matthew, Kendler, Kenneth S, Kinreich, Sivan, Kramer, John, Kuo, Sally I-Chun, Kuperman, Samuel, Lai, Dongbing, McIntosh, Andrew M, Meyers, Jacquelyn L, Plawecki, Martin H, Porjesz, Bernice, Porteous, David, Schuckit, Marc A, Su, Jinni, Zang, Yong, Palmer, Abraham A, Agrawal, Arpana, Clarke, Toni-Kim, and Edwards, Alexis C
Abstract: BackgroundStudies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.MethodsWe examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.ResultsIn COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10-16).ConclusionsAUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
Published: 2021

27. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Author: Munn-Chernoff, Melissa A, Johnson, Emma C, Chou, Yi-Ling, Coleman, Jonathan R I, Thornton, Laura M, Walters, Raymond K, Yilmaz, Zeynep, Baker, Jessica H, Hübel, Christopher, Gordon, Scott, Medland, Sarah E, Watson, Hunna J, Gaspar, Héléna A, Bryois, Julien, Hinney, Anke, Leppä, Virpi M, Mattheisen, Manuel, Ripke, Stephan, Yao, Shuyang, Giusti-Rodríguez, Paola, Hanscombe, Ken B, Adan, Roger A H, Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole A, Berrettini, Wade H, Boehm, Ilka, Boni, Claudette, Boraska Perica, Vesna, Buehren, Katharina, Burghardt, Roland, Cassina, Matteo, Cichon, Sven, Clementi, Maurizio, Cone, Roger D, Courtet, Philippe, Crow, Scott, Crowley, James J, Danner, Unna N, Davis, Oliver S P, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E, Dick, Danielle M, Dikeos, Dimitris, Dina, Christian, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Duncan, Laramie E, Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M, Fischer, Krista, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J, Forzan, Monica, Franklin, Christopher S, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos Mayora, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske G, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Huckins, Laura M, Hudson, James I, Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J H, Kennedy, James L, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klump, Kelly L, Knudsen, Gun Peggy S, La Via, Maria C, Le Hellard, Stephanie, Levitan, Robert D, Li, Dong, Lilenfeld, Lisa, Lin, Bochao Danae, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre J, Maj, Mario, Mannik, Katrin, Marsal, Sara, Marshall, Christian R, Mattingsdal, Morten, McDevitt, Sara, McGuffin, Peter, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen, Monteleone, Alessio Maria, Monteleone, Palmiero, Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, O'Toole, Julie K, Ophoff, Roel A, Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Pinto, Dalila, Rabionet, Raquel, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W, Schmidt, Ulrike, Schork, Nicholas J, Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P Eline, Slof-Op't Landt, Margarita C T, Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Szatkiewicz, Jin P, Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A, van Furth, Eric F, Wagner, Gudrun, Walton, Esther, Widen, Elisabeth, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W, Boden, Joseph M, Brandt, Harry, Crawford, Steven, Halmi, Katherine A, Horwood, L John, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Mitchell, James, Olsen, Catherine M, Pearson, John F, Pedersen, Nancy L, Strober, Michael, Werge, Thomas, Whiteman, David C, Woodside, D Blake, Grove, Jakob, Henders, Anjali K, Larsen, Janne T, Parker, Richard, Petersen, Liselotte V, Jordan, Jennifer, Kennedy, Martin A, Birgegård, Andreas, Lichtenstein, Paul, Norring, Claes, Landén, Mikael, Mortensen, Preben Bo, Polimanti, Renato, McClintick, Jeanette N, Adkins, Amy E, Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna M, Bigdeli, Tim B, Chen, Li-Shiun, Clarke, Toni-Kim, Degenhardt, Franziska, Docherty, Anna R, Edwards, Alexis C, Foo, Jerome C, Fox, Louis, Frank, Josef, Hack, Laura M, Hartmann, Annette M, Hartz, Sarah M, Heilmann-Heimbach, Stefanie, Hodgkinson, Colin, Hoffmann, Per, Hottenga, Jouke-Jan, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion S, Mbarek, Hamdi, McIntosh, Andrew M, McQueen, Matthew B, Meyers, Jacquelyn L, Milaneschi, Yuri, Palviainen, Teemu, Peterson, Roseann E, Ryu, Euijung, Saccone, Nancy L, Salvatore, Jessica E, Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley T, Wedow, Robbee, Wetherill, Leah, Wills, Amanda G, Zhou, Hang, Boardman, Jason D, Chen, Danfeng, Choi, Doo-Sup, Copeland, William E, Culverhouse, Robert C, Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W, Frye, Mark A, Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Koller, Gabriele, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T, Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison D, Nurnberger, John I, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D, Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc A, Soyka, Michael, Treutlein, Jens, Witt, Stephanie H, Wodarz, Norbert, Zill, Peter, Adkins, Daniel E, Boomsma, Dorret I, Bierut, Laura J, Brown, Sandra A, Bucholz, Kathleen K, Costello, E Jane, de Wit, Harriet, Diazgranados, Nancy, Eriksson, Johan G, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Goate, Alison M, Goldman, David, Grucza, Richard A, Hancock, Dana B, Harris, Kathleen Mullan, Hesselbrock, Victor, Hewitt, John K, Hopfer, Christian J, Iacono, William G, Johnson, Eric O, Karpyak, Victor M, Kendler, Kenneth S, Kranzler, Henry R, Krauter, Kenneth, Lind, Penelope A, McGue, Matt, MacKillop, James, Madden, Pamela A F, Maes, Hermine H, Magnusson, Patrik K E, Nelson, Elliot C, Nöthen, Markus M, Palmer, Abraham A, Penninx, Brenda W J H, Porjesz, Bernice, Rice, John P, Rietschel, Marcella, Riley, Brien P, Rose, Richard J, Shen, Pei-Hong, Silberg, Judy, Stallings, Michael C, Tarter, Ralph E, Vanyukov, Michael M, Vrieze, Scott, Wall, Tamara L, Whitfield, John B, Zhao, Hongyu, Neale, Benjamin M, Wade, Tracey D, Heath, Andrew C, Montgomery, Grant W, Martin, Nicholas G, Sullivan, Patrick F, Kaprio, Jaakko, Breen, Gerome, Gelernter, Joel, Edenberg, Howard J, Bulik, Cynthia M, Agrawal, Arpana, Munn-Chernoff, Melissa A, Johnson, Emma C, Chou, Yi-Ling, Coleman, Jonathan R I, Thornton, Laura M, Walters, Raymond K, Yilmaz, Zeynep, Baker, Jessica H, Hübel, Christopher, Gordon, Scott, Medland, Sarah E, Watson, Hunna J, Gaspar, Héléna A, Bryois, Julien, Hinney, Anke, Leppä, Virpi M, Mattheisen, Manuel, Ripke, Stephan, Yao, Shuyang, Giusti-Rodríguez, Paola, Hanscombe, Ken B, Adan, Roger A H, Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole A, Berrettini, Wade H, Boehm, Ilka, Boni, Claudette, Boraska Perica, Vesna, Buehren, Katharina, Burghardt, Roland, Cassina, Matteo, Cichon, Sven, Clementi, Maurizio, Cone, Roger D, Courtet, Philippe, Crow, Scott, Crowley, James J, Danner, Unna N, Davis, Oliver S P, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E, Dick, Danielle M, Dikeos, Dimitris, Dina, Christian, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Duncan, Laramie E, Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M, Fischer, Krista, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J, Forzan, Monica, Franklin, Christopher S, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos Mayora, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske G, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Huckins, Laura M, Hudson, James I, Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J H, Kennedy, James L, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klump, Kelly L, Knudsen, Gun Peggy S, La Via, Maria C, Le Hellard, Stephanie, Levitan, Robert D, Li, Dong, Lilenfeld, Lisa, Lin, Bochao Danae, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre J, Maj, Mario, Mannik, Katrin, Marsal, Sara, Marshall, Christian R, Mattingsdal, Morten, McDevitt, Sara, McGuffin, Peter, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen, Monteleone, Alessio Maria, Monteleone, Palmiero, Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, O'Toole, Julie K, Ophoff, Roel A, Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Pinto, Dalila, Rabionet, Raquel, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W, Schmidt, Ulrike, Schork, Nicholas J, Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P Eline, Slof-Op't Landt, Margarita C T, Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Szatkiewicz, Jin P, Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A, van Furth, Eric F, Wagner, Gudrun, Walton, Esther, Widen, Elisabeth, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W, Boden, Joseph M, Brandt, Harry, Crawford, Steven, Halmi, Katherine A, Horwood, L John, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Mitchell, James, Olsen, Catherine M, Pearson, John F, Pedersen, Nancy L, Strober, Michael, Werge, Thomas, Whiteman, David C, Woodside, D Blake, Grove, Jakob, Henders, Anjali K, Larsen, Janne T, Parker, Richard, Petersen, Liselotte V, Jordan, Jennifer, Kennedy, Martin A, Birgegård, Andreas, Lichtenstein, Paul, Norring, Claes, Landén, Mikael, Mortensen, Preben Bo, Polimanti, Renato, McClintick, Jeanette N, Adkins, Amy E, Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna M, Bigdeli, Tim B, Chen, Li-Shiun, Clarke, Toni-Kim, Degenhardt, Franziska, Docherty, Anna R, Edwards, Alexis C, Foo, Jerome C, Fox, Louis, Frank, Josef, Hack, Laura M, Hartmann, Annette M, Hartz, Sarah M, Heilmann-Heimbach, Stefanie, Hodgkinson, Colin, Hoffmann, Per, Hottenga, Jouke-Jan, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion S, Mbarek, Hamdi, McIntosh, Andrew M, McQueen, Matthew B, Meyers, Jacquelyn L, Milaneschi, Yuri, Palviainen, Teemu, Peterson, Roseann E, Ryu, Euijung, Saccone, Nancy L, Salvatore, Jessica E, Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley T, Wedow, Robbee, Wetherill, Leah, Wills, Amanda G, Zhou, Hang, Boardman, Jason D, Chen, Danfeng, Choi, Doo-Sup, Copeland, William E, Culverhouse, Robert C, Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W, Frye, Mark A, Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Koller, Gabriele, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T, Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison D, Nurnberger, John I, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D, Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc A, Soyka, Michael, Treutlein, Jens, Witt, Stephanie H, Wodarz, Norbert, Zill, Peter, Adkins, Daniel E, Boomsma, Dorret I, Bierut, Laura J, Brown, Sandra A, Bucholz, Kathleen K, Costello, E Jane, de Wit, Harriet, Diazgranados, Nancy, Eriksson, Johan G, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Goate, Alison M, Goldman, David, Grucza, Richard A, Hancock, Dana B, Harris, Kathleen Mullan, Hesselbrock, Victor, Hewitt, John K, Hopfer, Christian J, Iacono, William G, Johnson, Eric O, Karpyak, Victor M, Kendler, Kenneth S, Kranzler, Henry R, Krauter, Kenneth, Lind, Penelope A, McGue, Matt, MacKillop, James, Madden, Pamela A F, Maes, Hermine H, Magnusson, Patrik K E, Nelson, Elliot C, Nöthen, Markus M, Palmer, Abraham A, Penninx, Brenda W J H, Porjesz, Bernice, Rice, John P, Rietschel, Marcella, Riley, Brien P, Rose, Richard J, Shen, Pei-Hong, Silberg, Judy, Stallings, Michael C, Tarter, Ralph E, Vanyukov, Michael M, Vrieze, Scott, Wall, Tamara L, Whitfield, John B, Zhao, Hongyu, Neale, Benjamin M, Wade, Tracey D, Heath, Andrew C, Montgomery, Grant W, Martin, Nicholas G, Sullivan, Patrick F, Kaprio, Jaakko, Breen, Gerome, Gelernter, Joel, Edenberg, Howard J, Bulik, Cynthia M, and Agrawal, Arpana
Abstract: Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-sp
Published: 2021
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28. Integration of evidence across human and model organism studies: A meeting report.

Author: Palmer, Rohan HC, Palmer, Rohan HC, Johnson, Emma C, Won, Hyejung, Polimanti, Renato, Kapoor, Manav, Chitre, Apurva, Bogue, Molly A, Benca-Bachman, Chelsie E, Parker, Clarissa C, Verma, Anurag, Reynolds, Timothy, Ernst, Jason, Bray, Michael, Kwon, Soo Bin, Lai, Dongbing, Quach, Bryan C, Gaddis, Nathan C, Saba, Laura, Chen, Hao, Hawrylycz, Michael, Zhang, Shan, Zhou, Yuan, Mahaffey, Spencer, Fischer, Christian, Sanchez-Roige, Sandra, Bandrowski, Anita, Lu, Qing, Shen, Li, Philip, Vivek, Gelernter, Joel, Bierut, Laura J, Hancock, Dana B, Edenberg, Howard J, Johnson, Eric O, Nestler, Eric J, Barr, Peter B, Prins, Pjotr, Smith, Desmond J, Akbarian, Schahram, Thorgeirsson, Thorgeir, Walton, Dave, Baker, Erich, Jacobson, Daniel, Palmer, Abraham A, Miles, Michael, Chesler, Elissa J, Emerson, Jake, Agrawal, Arpana, Martone, Maryann, Williams, Robert W, Palmer, Rohan HC, Palmer, Rohan HC, Johnson, Emma C, Won, Hyejung, Polimanti, Renato, Kapoor, Manav, Chitre, Apurva, Bogue, Molly A, Benca-Bachman, Chelsie E, Parker, Clarissa C, Verma, Anurag, Reynolds, Timothy, Ernst, Jason, Bray, Michael, Kwon, Soo Bin, Lai, Dongbing, Quach, Bryan C, Gaddis, Nathan C, Saba, Laura, Chen, Hao, Hawrylycz, Michael, Zhang, Shan, Zhou, Yuan, Mahaffey, Spencer, Fischer, Christian, Sanchez-Roige, Sandra, Bandrowski, Anita, Lu, Qing, Shen, Li, Philip, Vivek, Gelernter, Joel, Bierut, Laura J, Hancock, Dana B, Edenberg, Howard J, Johnson, Eric O, Nestler, Eric J, Barr, Peter B, Prins, Pjotr, Smith, Desmond J, Akbarian, Schahram, Thorgeirsson, Thorgeir, Walton, Dave, Baker, Erich, Jacobson, Daniel, Palmer, Abraham A, Miles, Michael, Chesler, Elissa J, Emerson, Jake, Agrawal, Arpana, Martone, Maryann, and Williams, Robert W
Abstract: The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration-particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.
Published: 2021

29. Polygenic contributions to alcohol use and alcohol use disorders across population-based and clinically ascertained samples.

Author: Johnson, Emma C, Johnson, Emma C, Sanchez-Roige, Sandra, Acion, Laura, Adams, Mark J, Bucholz, Kathleen K, Chan, Grace, Chao, Michael J, Chorlian, David B, Dick, Danielle M, Edenberg, Howard J, Foroud, Tatiana, Hayward, Caroline, Heron, Jon, Hesselbrock, Victor, Hickman, Matthew, Kendler, Kenneth S, Kinreich, Sivan, Kramer, John, Kuo, Sally I-Chun, Kuperman, Samuel, Lai, Dongbing, McIntosh, Andrew M, Meyers, Jacquelyn L, Plawecki, Martin H, Porjesz, Bernice, Porteous, David, Schuckit, Marc A, Su, Jinni, Zang, Yong, Palmer, Abraham A, Agrawal, Arpana, Clarke, Toni-Kim, Edwards, Alexis C, Johnson, Emma C, Johnson, Emma C, Sanchez-Roige, Sandra, Acion, Laura, Adams, Mark J, Bucholz, Kathleen K, Chan, Grace, Chao, Michael J, Chorlian, David B, Dick, Danielle M, Edenberg, Howard J, Foroud, Tatiana, Hayward, Caroline, Heron, Jon, Hesselbrock, Victor, Hickman, Matthew, Kendler, Kenneth S, Kinreich, Sivan, Kramer, John, Kuo, Sally I-Chun, Kuperman, Samuel, Lai, Dongbing, McIntosh, Andrew M, Meyers, Jacquelyn L, Plawecki, Martin H, Porjesz, Bernice, Porteous, David, Schuckit, Marc A, Su, Jinni, Zang, Yong, Palmer, Abraham A, Agrawal, Arpana, Clarke, Toni-Kim, and Edwards, Alexis C
Abstract: BackgroundStudies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.MethodsWe examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.ResultsIn COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10-16).ConclusionsAUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
Published: 2021

30. Mapping Pathways by Which Genetic Risk Influences Adolescent Externalizing Behavior: The Interplay Between Externalizing Polygenic Risk Scores, Parental Knowledge, and Peer Substance Use.

Author: Kuo, Sally I-Chun, Kuo, Sally I-Chun, Salvatore, Jessica E, Barr, Peter B, Aliev, Fazil, Anokhin, Andrey, Bucholz, Kathleen K, Chan, Grace, Edenberg, Howard J, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John R, Lai, Dongbing, Mallard, Travis T, Nurnberger, John I, Pandey, Gayathri, Plawecki, Martin H, Sanchez-Roige, Sandra, Waldman, Irwin, Palmer, Abraham A, Externalizing Consortium, Dick, Danielle M, Kuo, Sally I-Chun, Kuo, Sally I-Chun, Salvatore, Jessica E, Barr, Peter B, Aliev, Fazil, Anokhin, Andrey, Bucholz, Kathleen K, Chan, Grace, Edenberg, Howard J, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John R, Lai, Dongbing, Mallard, Travis T, Nurnberger, John I, Pandey, Gayathri, Plawecki, Martin H, Sanchez-Roige, Sandra, Waldman, Irwin, Palmer, Abraham A, Externalizing Consortium, and Dick, Danielle M
Abstract: Genetic predispositions and environmental influences both play an important role in adolescent externalizing behavior; however, they are not always independent. To elucidate gene-environment interplay, we examined the interrelationships between externalizing polygenic risk scores, parental knowledge, and peer substance use in impacting adolescent externalizing behavior across two time-points in a high-risk longitudinal sample of 1,200 adolescents (764 European and 436 African ancestry; Mage = 12.99) from the Collaborative Study on the Genetics of Alcoholism. Results from multivariate path analysis indicated that externalizing polygenic scores were directly associated with adolescent externalizing behavior but also indirectly via peer substance use, in the European ancestry sample. No significant polygenic association nor indirect effects of genetic risk were observed in the African ancestry group, likely due to more limited power. Our findings underscore the importance of gene-environment interplay and suggest peer substance use may be a mechanism through which genetic risk influences adolescent externalizing behavior.
Published: 2021

31. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Author: Munn-Chernoff, Melissa A, Johnson, Emma C, Chou, Yi-Ling, Coleman, Jonathan R I, Thornton, Laura M, Walters, Raymond K, Yilmaz, Zeynep, Baker, Jessica H, Hübel, Christopher, Gordon, Scott, Medland, Sarah E, Watson, Hunna J, Gaspar, Héléna A, Bryois, Julien, Hinney, Anke, Leppä, Virpi M, Mattheisen, Manuel, Ripke, Stephan, Yao, Shuyang, Giusti-Rodríguez, Paola, Hanscombe, Ken B, Adan, Roger A H, Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole A, Berrettini, Wade H, Boehm, Ilka, Boni, Claudette, Boraska Perica, Vesna, Buehren, Katharina, Burghardt, Roland, Cassina, Matteo, Cichon, Sven, Clementi, Maurizio, Cone, Roger D, Courtet, Philippe, Crow, Scott, Crowley, James J, Danner, Unna N, Davis, Oliver S P, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E, Dick, Danielle M, Dikeos, Dimitris, Dina, Christian, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Duncan, Laramie E, Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M, Fischer, Krista, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J, Forzan, Monica, Franklin, Christopher S, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos Mayora, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske G, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Huckins, Laura M, Hudson, James I, Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J H, Kennedy, James L, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klump, Kelly L, Knudsen, Gun Peggy S, La Via, Maria C, Le Hellard, Stephanie, Levitan, Robert D, Li, Dong, Lilenfeld, Lisa, Lin, Bochao Danae, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre J, Maj, Mario, Mannik, Katrin, Marsal, Sara, Marshall, Christian R, Mattingsdal, Morten, McDevitt, Sara, McGuffin, Peter, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen, Monteleone, Alessio Maria, Monteleone, Palmiero, Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, O'Toole, Julie K, Ophoff, Roel A, Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Pinto, Dalila, Rabionet, Raquel, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W, Schmidt, Ulrike, Schork, Nicholas J, Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P Eline, Slof-Op't Landt, Margarita C T, Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Szatkiewicz, Jin P, Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A, van Furth, Eric F, Wagner, Gudrun, Walton, Esther, Widen, Elisabeth, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W, Boden, Joseph M, Brandt, Harry, Crawford, Steven, Halmi, Katherine A, Horwood, L John, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Mitchell, James, Olsen, Catherine M, Pearson, John F, Pedersen, Nancy L, Strober, Michael, Werge, Thomas, Whiteman, David C, Woodside, D Blake, Grove, Jakob, Henders, Anjali K, Larsen, Janne T, Parker, Richard, Petersen, Liselotte V, Jordan, Jennifer, Kennedy, Martin A, Birgegård, Andreas, Lichtenstein, Paul, Norring, Claes, Landén, Mikael, Mortensen, Preben Bo, Polimanti, Renato, McClintick, Jeanette N, Adkins, Amy E, Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna M, Bigdeli, Tim B, Chen, Li-Shiun, Clarke, Toni-Kim, Degenhardt, Franziska, Docherty, Anna R, Edwards, Alexis C, Foo, Jerome C, Fox, Louis, Frank, Josef, Hack, Laura M, Hartmann, Annette M, Hartz, Sarah M, Heilmann-Heimbach, Stefanie, Hodgkinson, Colin, Hoffmann, Per, Hottenga, Jouke-Jan, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion S, Mbarek, Hamdi, McIntosh, Andrew M, McQueen, Matthew B, Meyers, Jacquelyn L, Milaneschi, Yuri, Palviainen, Teemu, Peterson, Roseann E, Ryu, Euijung, Saccone, Nancy L, Salvatore, Jessica E, Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley T, Wedow, Robbee, Wetherill, Leah, Wills, Amanda G, Zhou, Hang, Boardman, Jason D, Chen, Danfeng, Choi, Doo-Sup, Copeland, William E, Culverhouse, Robert C, Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W, Frye, Mark A, Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Koller, Gabriele, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T, Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison D, Nurnberger, John I, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D, Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc A, Soyka, Michael, Treutlein, Jens, Witt, Stephanie H, Wodarz, Norbert, Zill, Peter, Adkins, Daniel E, Boomsma, Dorret I, Bierut, Laura J, Brown, Sandra A, Bucholz, Kathleen K, Costello, E Jane, de Wit, Harriet, Diazgranados, Nancy, Eriksson, Johan G, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Goate, Alison M, Goldman, David, Grucza, Richard A, Hancock, Dana B, Harris, Kathleen Mullan, Hesselbrock, Victor, Hewitt, John K, Hopfer, Christian J, Iacono, William G, Johnson, Eric O, Karpyak, Victor M, Kendler, Kenneth S, Kranzler, Henry R, Krauter, Kenneth, Lind, Penelope A, McGue, Matt, MacKillop, James, Madden, Pamela A F, Maes, Hermine H, Magnusson, Patrik K E, Nelson, Elliot C, Nöthen, Markus M, Palmer, Abraham A, Penninx, Brenda W J H, Porjesz, Bernice, Rice, John P, Rietschel, Marcella, Riley, Brien P, Rose, Richard J, Shen, Pei-Hong, Silberg, Judy, Stallings, Michael C, Tarter, Ralph E, Vanyukov, Michael M, Vrieze, Scott, Wall, Tamara L, Whitfield, John B, Zhao, Hongyu, Neale, Benjamin M, Wade, Tracey D, Heath, Andrew C, Montgomery, Grant W, Martin, Nicholas G, Sullivan, Patrick F, Kaprio, Jaakko, Breen, Gerome, Gelernter, Joel, Edenberg, Howard J, Bulik, Cynthia M, Agrawal, Arpana, Munn-Chernoff, Melissa A, Johnson, Emma C, Chou, Yi-Ling, Coleman, Jonathan R I, Thornton, Laura M, Walters, Raymond K, Yilmaz, Zeynep, Baker, Jessica H, Hübel, Christopher, Gordon, Scott, Medland, Sarah E, Watson, Hunna J, Gaspar, Héléna A, Bryois, Julien, Hinney, Anke, Leppä, Virpi M, Mattheisen, Manuel, Ripke, Stephan, Yao, Shuyang, Giusti-Rodríguez, Paola, Hanscombe, Ken B, Adan, Roger A H, Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole A, Berrettini, Wade H, Boehm, Ilka, Boni, Claudette, Boraska Perica, Vesna, Buehren, Katharina, Burghardt, Roland, Cassina, Matteo, Cichon, Sven, Clementi, Maurizio, Cone, Roger D, Courtet, Philippe, Crow, Scott, Crowley, James J, Danner, Unna N, Davis, Oliver S P, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E, Dick, Danielle M, Dikeos, Dimitris, Dina, Christian, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Duncan, Laramie E, Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M, Fischer, Krista, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J, Forzan, Monica, Franklin, Christopher S, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos Mayora, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske G, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Huckins, Laura M, Hudson, James I, Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J H, Kennedy, James L, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klump, Kelly L, Knudsen, Gun Peggy S, La Via, Maria C, Le Hellard, Stephanie, Levitan, Robert D, Li, Dong, Lilenfeld, Lisa, Lin, Bochao Danae, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre J, Maj, Mario, Mannik, Katrin, Marsal, Sara, Marshall, Christian R, Mattingsdal, Morten, McDevitt, Sara, McGuffin, Peter, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen, Monteleone, Alessio Maria, Monteleone, Palmiero, Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, O'Toole, Julie K, Ophoff, Roel A, Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Pinto, Dalila, Rabionet, Raquel, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W, Schmidt, Ulrike, Schork, Nicholas J, Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P Eline, Slof-Op't Landt, Margarita C T, Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Szatkiewicz, Jin P, Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A, van Furth, Eric F, Wagner, Gudrun, Walton, Esther, Widen, Elisabeth, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W, Boden, Joseph M, Brandt, Harry, Crawford, Steven, Halmi, Katherine A, Horwood, L John, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Mitchell, James, Olsen, Catherine M, Pearson, John F, Pedersen, Nancy L, Strober, Michael, Werge, Thomas, Whiteman, David C, Woodside, D Blake, Grove, Jakob, Henders, Anjali K, Larsen, Janne T, Parker, Richard, Petersen, Liselotte V, Jordan, Jennifer, Kennedy, Martin A, Birgegård, Andreas, Lichtenstein, Paul, Norring, Claes, Landén, Mikael, Mortensen, Preben Bo, Polimanti, Renato, McClintick, Jeanette N, Adkins, Amy E, Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna M, Bigdeli, Tim B, Chen, Li-Shiun, Clarke, Toni-Kim, Degenhardt, Franziska, Docherty, Anna R, Edwards, Alexis C, Foo, Jerome C, Fox, Louis, Frank, Josef, Hack, Laura M, Hartmann, Annette M, Hartz, Sarah M, Heilmann-Heimbach, Stefanie, Hodgkinson, Colin, Hoffmann, Per, Hottenga, Jouke-Jan, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion S, Mbarek, Hamdi, McIntosh, Andrew M, McQueen, Matthew B, Meyers, Jacquelyn L, Milaneschi, Yuri, Palviainen, Teemu, Peterson, Roseann E, Ryu, Euijung, Saccone, Nancy L, Salvatore, Jessica E, Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley T, Wedow, Robbee, Wetherill, Leah, Wills, Amanda G, Zhou, Hang, Boardman, Jason D, Chen, Danfeng, Choi, Doo-Sup, Copeland, William E, Culverhouse, Robert C, Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W, Frye, Mark A, Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Koller, Gabriele, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T, Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison D, Nurnberger, John I, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D, Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc A, Soyka, Michael, Treutlein, Jens, Witt, Stephanie H, Wodarz, Norbert, Zill, Peter, Adkins, Daniel E, Boomsma, Dorret I, Bierut, Laura J, Brown, Sandra A, Bucholz, Kathleen K, Costello, E Jane, de Wit, Harriet, Diazgranados, Nancy, Eriksson, Johan G, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Goate, Alison M, Goldman, David, Grucza, Richard A, Hancock, Dana B, Harris, Kathleen Mullan, Hesselbrock, Victor, Hewitt, John K, Hopfer, Christian J, Iacono, William G, Johnson, Eric O, Karpyak, Victor M, Kendler, Kenneth S, Kranzler, Henry R, Krauter, Kenneth, Lind, Penelope A, McGue, Matt, MacKillop, James, Madden, Pamela A F, Maes, Hermine H, Magnusson, Patrik K E, Nelson, Elliot C, Nöthen, Markus M, Palmer, Abraham A, Penninx, Brenda W J H, Porjesz, Bernice, Rice, John P, Rietschel, Marcella, Riley, Brien P, Rose, Richard J, Shen, Pei-Hong, Silberg, Judy, Stallings, Michael C, Tarter, Ralph E, Vanyukov, Michael M, Vrieze, Scott, Wall, Tamara L, Whitfield, John B, Zhao, Hongyu, Neale, Benjamin M, Wade, Tracey D, Heath, Andrew C, Montgomery, Grant W, Martin, Nicholas G, Sullivan, Patrick F, Kaprio, Jaakko, Breen, Gerome, Gelernter, Joel, Edenberg, Howard J, Bulik, Cynthia M, and Agrawal, Arpana
Abstract: Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-sp
Published: 2021
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32. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author: Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, de Boer, Rudolf A, de Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela A F, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D P, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renstrom, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, van der Leij, Andries R, van der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin N A, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, van der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, Howson, Joanna M M, Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, de Boer, Rudolf A, de Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela A F, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D P, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renstrom, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, van der Leij, Andries R, van der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin N A, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, van der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, and Howson, Joanna M M
Abstract: Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
Published: 2020
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33. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author: Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, de Boer, Rudolf A, de Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela A F, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D P, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renstrom, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, van der Leij, Andries R, van der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin N A, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, van der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, Howson, Joanna M M, Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, de Boer, Rudolf A, de Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela A F, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D P, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renstrom, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, van der Leij, Andries R, van der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin N A, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, van der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, and Howson, Joanna M M
Abstract: Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
Published: 2020
Full Text: View/download PDF

34. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author: Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, de Boer, Rudolf A, de Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela A F, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D P, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renstrom, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, van der Leij, Andries R, van der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin N A, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, van der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, Howson, Joanna M M, Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, de Boer, Rudolf A, de Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela A F, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D P, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renstrom, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, van der Leij, Andries R, van der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin N A, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, van der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, and Howson, Joanna M M
Abstract: Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
Published: 2020
Full Text: View/download PDF

35. A large-scale genome-wide association study meta-analysis of cannabis use disorder.

Author: Johnson, Emma C, Johnson, Emma C, Demontis, Ditte, Thorgeirsson, Thorgeir E, Walters, Raymond K, Polimanti, Renato, Hatoum, Alexander S, Sanchez-Roige, Sandra, Paul, Sarah E, Wendt, Frank R, Clarke, Toni-Kim, Lai, Dongbing, Reginsson, Gunnar W, Zhou, Hang, He, June, Baranger, David AA, Gudbjartsson, Daniel F, Wedow, Robbee, Adkins, Daniel E, Adkins, Amy E, Alexander, Jeffry, Bacanu, Silviu-Alin, Bigdeli, Tim B, Boden, Joseph, Brown, Sandra A, Bucholz, Kathleen K, Bybjerg-Grauholm, Jonas, Corley, Robin P, Degenhardt, Louisa, Dick, Danielle M, Domingue, Benjamin W, Fox, Louis, Goate, Alison M, Gordon, Scott D, Hack, Laura M, Hancock, Dana B, Hartz, Sarah M, Hickie, Ian B, Hougaard, David M, Krauter, Kenneth, Lind, Penelope A, McClintick, Jeanette N, McQueen, Matthew B, Meyers, Jacquelyn L, Montgomery, Grant W, Mors, Ole, Mortensen, Preben B, Nordentoft, Merete, Pearson, John F, Peterson, Roseann E, Reynolds, Maureen D, Rice, John P, Runarsdottir, Valgerdur, Saccone, Nancy L, Sherva, Richard, Silberg, Judy L, Tarter, Ralph E, Tyrfingsson, Thorarinn, Wall, Tamara L, Webb, Bradley T, Werge, Thomas, Wetherill, Leah, Wright, Margaret J, Zellers, Stephanie, Adams, Mark J, Bierut, Laura J, Boardman, Jason D, Copeland, William E, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Grucza, Richard A, Harris, Kathleen Mullan, Heath, Andrew C, Hesselbrock, Victor, Hewitt, John K, Hopfer, Christian J, Horwood, John, Iacono, William G, Johnson, Eric O, Kendler, Kenneth S, Kennedy, Martin A, Kranzler, Henry R, Madden, Pamela AF, Maes, Hermine H, Maher, Brion S, Martin, Nicholas G, McGue, Matthew, McIntosh, Andrew M, Medland, Sarah E, Nelson, Elliot C, Porjesz, Bernice, Riley, Brien P, Stallings, Michael C, Vanyukov, Michael M, Vrieze, Scott, Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Davis, Lea K, Bogdan, Ryan, Gelernter, Joel, Edenberg, Howard J, Johnson, Emma C, Johnson, Emma C, Demontis, Ditte, Thorgeirsson, Thorgeir E, Walters, Raymond K, Polimanti, Renato, Hatoum, Alexander S, Sanchez-Roige, Sandra, Paul, Sarah E, Wendt, Frank R, Clarke, Toni-Kim, Lai, Dongbing, Reginsson, Gunnar W, Zhou, Hang, He, June, Baranger, David AA, Gudbjartsson, Daniel F, Wedow, Robbee, Adkins, Daniel E, Adkins, Amy E, Alexander, Jeffry, Bacanu, Silviu-Alin, Bigdeli, Tim B, Boden, Joseph, Brown, Sandra A, Bucholz, Kathleen K, Bybjerg-Grauholm, Jonas, Corley, Robin P, Degenhardt, Louisa, Dick, Danielle M, Domingue, Benjamin W, Fox, Louis, Goate, Alison M, Gordon, Scott D, Hack, Laura M, Hancock, Dana B, Hartz, Sarah M, Hickie, Ian B, Hougaard, David M, Krauter, Kenneth, Lind, Penelope A, McClintick, Jeanette N, McQueen, Matthew B, Meyers, Jacquelyn L, Montgomery, Grant W, Mors, Ole, Mortensen, Preben B, Nordentoft, Merete, Pearson, John F, Peterson, Roseann E, Reynolds, Maureen D, Rice, John P, Runarsdottir, Valgerdur, Saccone, Nancy L, Sherva, Richard, Silberg, Judy L, Tarter, Ralph E, Tyrfingsson, Thorarinn, Wall, Tamara L, Webb, Bradley T, Werge, Thomas, Wetherill, Leah, Wright, Margaret J, Zellers, Stephanie, Adams, Mark J, Bierut, Laura J, Boardman, Jason D, Copeland, William E, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Grucza, Richard A, Harris, Kathleen Mullan, Heath, Andrew C, Hesselbrock, Victor, Hewitt, John K, Hopfer, Christian J, Horwood, John, Iacono, William G, Johnson, Eric O, Kendler, Kenneth S, Kennedy, Martin A, Kranzler, Henry R, Madden, Pamela AF, Maes, Hermine H, Maher, Brion S, Martin, Nicholas G, McGue, Matthew, McIntosh, Andrew M, Medland, Sarah E, Nelson, Elliot C, Porjesz, Bernice, Riley, Brien P, Stallings, Michael C, Vanyukov, Michael M, Vrieze, Scott, Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Davis, Lea K, Bogdan, Ryan, Gelernter, Joel, and Edenberg, Howard J
Abstract: BackgroundVariation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.MethodsTo conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.FindingsWe identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.InterpretationThese findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between gen
Published: 2020

36. A large-scale genome-wide association study meta-analysis of cannabis use disorder.

Author: Johnson, Emma C, Johnson, Emma C, Demontis, Ditte, Thorgeirsson, Thorgeir E, Walters, Raymond K, Polimanti, Renato, Hatoum, Alexander S, Sanchez-Roige, Sandra, Paul, Sarah E, Wendt, Frank R, Clarke, Toni-Kim, Lai, Dongbing, Reginsson, Gunnar W, Zhou, Hang, He, June, Baranger, David AA, Gudbjartsson, Daniel F, Wedow, Robbee, Adkins, Daniel E, Adkins, Amy E, Alexander, Jeffry, Bacanu, Silviu-Alin, Bigdeli, Tim B, Boden, Joseph, Brown, Sandra A, Bucholz, Kathleen K, Bybjerg-Grauholm, Jonas, Corley, Robin P, Degenhardt, Louisa, Dick, Danielle M, Domingue, Benjamin W, Fox, Louis, Goate, Alison M, Gordon, Scott D, Hack, Laura M, Hancock, Dana B, Hartz, Sarah M, Hickie, Ian B, Hougaard, David M, Krauter, Kenneth, Lind, Penelope A, McClintick, Jeanette N, McQueen, Matthew B, Meyers, Jacquelyn L, Montgomery, Grant W, Mors, Ole, Mortensen, Preben B, Nordentoft, Merete, Pearson, John F, Peterson, Roseann E, Reynolds, Maureen D, Rice, John P, Runarsdottir, Valgerdur, Saccone, Nancy L, Sherva, Richard, Silberg, Judy L, Tarter, Ralph E, Tyrfingsson, Thorarinn, Wall, Tamara L, Webb, Bradley T, Werge, Thomas, Wetherill, Leah, Wright, Margaret J, Zellers, Stephanie, Adams, Mark J, Bierut, Laura J, Boardman, Jason D, Copeland, William E, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Grucza, Richard A, Harris, Kathleen Mullan, Heath, Andrew C, Hesselbrock, Victor, Hewitt, John K, Hopfer, Christian J, Horwood, John, Iacono, William G, Johnson, Eric O, Kendler, Kenneth S, Kennedy, Martin A, Kranzler, Henry R, Madden, Pamela AF, Maes, Hermine H, Maher, Brion S, Martin, Nicholas G, McGue, Matthew, McIntosh, Andrew M, Medland, Sarah E, Nelson, Elliot C, Porjesz, Bernice, Riley, Brien P, Stallings, Michael C, Vanyukov, Michael M, Vrieze, Scott, Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Davis, Lea K, Bogdan, Ryan, Gelernter, Joel, Edenberg, Howard J, Johnson, Emma C, Johnson, Emma C, Demontis, Ditte, Thorgeirsson, Thorgeir E, Walters, Raymond K, Polimanti, Renato, Hatoum, Alexander S, Sanchez-Roige, Sandra, Paul, Sarah E, Wendt, Frank R, Clarke, Toni-Kim, Lai, Dongbing, Reginsson, Gunnar W, Zhou, Hang, He, June, Baranger, David AA, Gudbjartsson, Daniel F, Wedow, Robbee, Adkins, Daniel E, Adkins, Amy E, Alexander, Jeffry, Bacanu, Silviu-Alin, Bigdeli, Tim B, Boden, Joseph, Brown, Sandra A, Bucholz, Kathleen K, Bybjerg-Grauholm, Jonas, Corley, Robin P, Degenhardt, Louisa, Dick, Danielle M, Domingue, Benjamin W, Fox, Louis, Goate, Alison M, Gordon, Scott D, Hack, Laura M, Hancock, Dana B, Hartz, Sarah M, Hickie, Ian B, Hougaard, David M, Krauter, Kenneth, Lind, Penelope A, McClintick, Jeanette N, McQueen, Matthew B, Meyers, Jacquelyn L, Montgomery, Grant W, Mors, Ole, Mortensen, Preben B, Nordentoft, Merete, Pearson, John F, Peterson, Roseann E, Reynolds, Maureen D, Rice, John P, Runarsdottir, Valgerdur, Saccone, Nancy L, Sherva, Richard, Silberg, Judy L, Tarter, Ralph E, Tyrfingsson, Thorarinn, Wall, Tamara L, Webb, Bradley T, Werge, Thomas, Wetherill, Leah, Wright, Margaret J, Zellers, Stephanie, Adams, Mark J, Bierut, Laura J, Boardman, Jason D, Copeland, William E, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Grucza, Richard A, Harris, Kathleen Mullan, Heath, Andrew C, Hesselbrock, Victor, Hewitt, John K, Hopfer, Christian J, Horwood, John, Iacono, William G, Johnson, Eric O, Kendler, Kenneth S, Kennedy, Martin A, Kranzler, Henry R, Madden, Pamela AF, Maes, Hermine H, Maher, Brion S, Martin, Nicholas G, McGue, Matthew, McIntosh, Andrew M, Medland, Sarah E, Nelson, Elliot C, Porjesz, Bernice, Riley, Brien P, Stallings, Michael C, Vanyukov, Michael M, Vrieze, Scott, Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Davis, Lea K, Bogdan, Ryan, Gelernter, Joel, and Edenberg, Howard J
Abstract: BackgroundVariation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.MethodsTo conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.FindingsWe identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.InterpretationThese findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between gen
Published: 2020

37. Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

Author: Polimanti, Renato, Polimanti, Renato, Walters, Raymond K, Johnson, Emma C, McClintick, Jeanette N, Adkins, Amy E, Adkins, Daniel E, Bacanu, Silviu-Alin, Bierut, Laura J, Bigdeli, Tim B, Brown, Sandra, Bucholz, Kathleen K, Copeland, William E, Costello, E Jane, Degenhardt, Louisa, Farrer, Lindsay A, Foroud, Tatiana M, Fox, Louis, Goate, Alison M, Grucza, Richard, Hack, Laura M, Hancock, Dana B, Hartz, Sarah M, Heath, Andrew C, Hewitt, John K, Hopfer, Christian J, Johnson, Eric O, Kendler, Kenneth S, Kranzler, Henry R, Krauter, Kenneth, Lai, Dongbing, Madden, Pamela AF, Martin, Nicholas G, Maes, Hermine H, Nelson, Elliot C, Peterson, Roseann E, Porjesz, Bernice, Riley, Brien P, Saccone, Nancy, Stallings, Michael, Wall, Tamara L, Webb, Bradley T, Wetherill, Leah, Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Edenberg, Howard J, Agrawal, Arpana, Gelernter, Joel, Polimanti, Renato, Polimanti, Renato, Walters, Raymond K, Johnson, Emma C, McClintick, Jeanette N, Adkins, Amy E, Adkins, Daniel E, Bacanu, Silviu-Alin, Bierut, Laura J, Bigdeli, Tim B, Brown, Sandra, Bucholz, Kathleen K, Copeland, William E, Costello, E Jane, Degenhardt, Louisa, Farrer, Lindsay A, Foroud, Tatiana M, Fox, Louis, Goate, Alison M, Grucza, Richard, Hack, Laura M, Hancock, Dana B, Hartz, Sarah M, Heath, Andrew C, Hewitt, John K, Hopfer, Christian J, Johnson, Eric O, Kendler, Kenneth S, Kranzler, Henry R, Krauter, Kenneth, Lai, Dongbing, Madden, Pamela AF, Martin, Nicholas G, Maes, Hermine H, Nelson, Elliot C, Peterson, Roseann E, Porjesz, Bernice, Riley, Brien P, Saccone, Nancy, Stallings, Michael, Wall, Tamara L, Webb, Bradley T, Wetherill, Leah, Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Edenberg, Howard J, Agrawal, Arpana, and Gelernter, Joel
Abstract: To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.
Published: 2020

38. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author: Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, de Boer, Rudolf A, de Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela A F, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D P, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renstrom, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, van der Leij, Andries R, van der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin N A, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, van der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, Howson, Joanna M M, Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, de Boer, Rudolf A, de Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela A F, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D P, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renstrom, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, van der Leij, Andries R, van der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin N A, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, van der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, and Howson, Joanna M M
Abstract: Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
Published: 2020
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39. A large-scale genome-wide association study meta-analysis of cannabis use disorder

Author: Johnson, Emma C., Demontis, Ditte, Thorgeirsson, Thorgeir E., Walters, Raymond K., Polimanti, Renato, Hatoum, Alexander S., Sanchez-Roige, Sandra, Paul, Sarah E., Wendt, Frank R., Clarke, Toni Kim, Lai, Dongbing, Reginsson, Gunnar W., Zhou, Hang, He, June, Baranger, David A.A., Gudbjartsson, Daniel F., Wedow, Robbee, Adkins, Daniel E., Adkins, Amy E., Alexander, Jeffry, Bacanu, Silviu Alin, Bigdeli, Tim B., Boden, Joseph, Brown, Sandra A., Bucholz, Kathleen K., Bybjerg-Grauholm, Jonas, Corley, Robin P., Degenhardt, Louisa, Dick, Danielle M., Domingue, Benjamin W., Fox, Louis, Goate, Alison M., Gordon, Scott D., Hack, Laura M., Hancock, Dana B., Hartz, Sarah M., Hickie, Ian B., Hougaard, David M., Krauter, Kenneth, Lind, Penelope A., McClintick, Jeanette N., McQueen, Matthew B., Meyers, Jacquelyn L., Montgomery, Grant W., Mors, Ole, Mortensen, Preben B., Nordentoft, Merete, Pearson, John F., Peterson, Roseann E., Werge, Thomas, Johnson, Emma C., Demontis, Ditte, Thorgeirsson, Thorgeir E., Walters, Raymond K., Polimanti, Renato, Hatoum, Alexander S., Sanchez-Roige, Sandra, Paul, Sarah E., Wendt, Frank R., Clarke, Toni Kim, Lai, Dongbing, Reginsson, Gunnar W., Zhou, Hang, He, June, Baranger, David A.A., Gudbjartsson, Daniel F., Wedow, Robbee, Adkins, Daniel E., Adkins, Amy E., Alexander, Jeffry, Bacanu, Silviu Alin, Bigdeli, Tim B., Boden, Joseph, Brown, Sandra A., Bucholz, Kathleen K., Bybjerg-Grauholm, Jonas, Corley, Robin P., Degenhardt, Louisa, Dick, Danielle M., Domingue, Benjamin W., Fox, Louis, Goate, Alison M., Gordon, Scott D., Hack, Laura M., Hancock, Dana B., Hartz, Sarah M., Hickie, Ian B., Hougaard, David M., Krauter, Kenneth, Lind, Penelope A., McClintick, Jeanette N., McQueen, Matthew B., Meyers, Jacquelyn L., Montgomery, Grant W., Mors, Ole, Mortensen, Preben B., Nordentoft, Merete, Pearson, John F., Peterson, Roseann E., and Werge, Thomas
Abstract: Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10−9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10−9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10−21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with oth
Published: 2020

40. Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

Author: Munn-Chernoff, Melissa A., Johnson, Emma C., Chou, Yi Ling, Coleman, Jonathan R.I., Thornton, Laura M., Walters, Raymond K., Yilmaz, Zeynep, Baker, Jessica H., Hübel, Christopher, Gordon, Scott, Medland, Sarah E., Watson, Hunna J., Gaspar, Héléna A., Bryois, Julien, Hinney, Anke, Leppä, Virpi M., Mattheisen, Manuel, Ripke, Stephan, Yao, Shuyang, Giusti-Rodríguez, Paola, Hanscombe, Ken B., Adan, Roger A.H., Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole A., Berrettini, Wade H., Boehm, Ilka, Boni, Claudette, Boraska Perica, Vesna, Buehren, Katharina, Burghardt, Roland, Cassina, Matteo, Cichon, Sven, Clementi, Maurizio, Cone, Roger D., Courtet, Philippe, Crow, Scott, Crowley, James J., Danner, Unna N., Davis, Oliver S.P., de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E., Dick, Danielle M., Dikeos, Dimitris, Dina, Christian, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Duncan, Laramie E., Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M., Fischer, Krista, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J., Forzan, Monica, Franklin, Christopher S., Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos Mayora, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske G., Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Huckins, Laura M., Hudson, James I., Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J.H., Kennedy, James L., Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl Ri, Klump, Kelly L., Knudsen, Gun Peggy S., La Via, Maria C., Le Hellard, Stephanie, Levitan, Robert D., Li, Dong, Lilenfeld, Lisa, Lin, Bochao Danae, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre J., Maj, Mario, Mannik, Katrin, Marsal, Sara, Marshall, Christian R., Mattingsdal, Morten, McDevitt, Sara, McGuffin, Peter, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen, Monteleone, Alessio Maria, Monteleone, Palmiero, Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, O'Toole, Julie K., Ophoff, Roel A., Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Pinto, Dalila, Rabionet, Raquel, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W., Schmidt, Ulrike, Schork, Nicholas J., Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P. Eline, Slof-Op't Landt, Margarita C.T., Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Szatkiewicz, Jin P., Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A., van Furth, Eric F., Wagner, Gudrun, Walton, Esther, Widen, Elisabeth, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W., Boden, Joseph M., Brandt, Harry, Crawford, Steven, Halmi, Katherine A., Horwood, L. John, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Mitchell, James, Olsen, Catherine M., Pearson, John F., Pedersen, Nancy L., Strober, Michael, Werge, Thomas, Whiteman, David C., Woodside, D. Blake, Grove, Jakob, Henders, Anjali K., Larsen, Janne T., Parker, Richard, Petersen, Liselotte V., Jordan, Jennifer, Kennedy, Martin A., Birgegård, Andreas, Lichtenstein, Paul, Norring, Claes, Landén, Mikael, Mortensen, Preben Bo, Polimanti, Renato, McClintick, Jeanette N., Adkins, Amy E., Aliev, Fazil, Bacanu, Silviu Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna M., Bigdeli, Tim B., Chen, Li Shiun, Clarke, Toni Kim, Degenhardt, Franziska, Docherty, Anna R., Edwards, Alexis C., Foo, Jerome C., Fox, Louis, Frank, Josef, Hack, Laura M., Hartmann, Annette M., Hartz, Sarah M., Heilmann-Heimbach, Stefanie, Hodgkinson, Colin, Hoffmann, Per, Hottenga, Jouke Jan, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion S., Mbarek, Hamdi, McIntosh, Andrew M., McQueen, Matthew B., Meyers, Jacquelyn L., Milaneschi, Yuri, Palviainen, Teemu, Peterson, Roseann E., Ryu, Euijung, Saccone, Nancy L., Salvatore, Jessica E., Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen Chyong, Webb, Bradley T., Wedow, Robbee, Wetherill, Leah, Wills, Amanda G., Zhou, Hang, Boardman, Jason D., Chen, Danfeng, Choi, Doo Sup, Copeland, William E., Culverhouse, Robert C., Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W., Frye, Mark A., Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Koller, Gabriele, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T., Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison D., Nurnberger, John I., Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D., Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc A., Soyka, Michael, Treutlein, Jens, Witt, Stephanie H., Wodarz, Norbert, Zill, Peter, Adkins, Daniel E., Boomsma, Dorret I., Bierut, Laura J., Brown, Sandra A., Bucholz, Kathleen K., Costello, E. Jane, de Wit, Harriet, Diazgranados, Nancy, Eriksson, Johan G., Farrer, Lindsay A., Foroud, Tatiana M., Gillespie, Nathan A., Goate, Alison M., Goldman, David, Grucza, Richard A., Hancock, Dana B., Harris, Kathleen Mullan, Hesselbrock, Victor, Hewitt, John K., Hopfer, Christian J., Iacono, William G., Johnson, Eric O., Karpyak, Victor M., Kendler, Kenneth S., Kranzler, Henry R., Krauter, Kenneth, Lind, Penelope A., McGue, Matt, MacKillop, James, Madden, Pamela A.F., Maes, Hermine H., Magnusson, Patrik K.E., Nelson, Elliot C., Nöthen, Markus M., Palmer, Abraham A., Penninx, Brenda W.J.H., Porjesz, Bernice, Rice, John P., Rietschel, Marcella, Riley, Brien P., Rose, Richard J., Shen, Pei Hong, Silberg, Judy, Stallings, Michael C., Tarter, Ralph E., Vanyukov, Michael M., Vrieze, Scott, Wall, Tamara L., Whitfield, John B., Zhao, Hongyu, Neale, Benjamin M., Wade, Tracey D., Heath, Andrew C., Montgomery, Grant W., Martin, Nicholas G., Sullivan, Patrick F., Kaprio, Jaakko, Breen, Gerome, Gelernter, Joel, Edenberg, Howard J., Bulik, Cynthia M., Agrawal, Arpana, Munn-Chernoff, Melissa A., Johnson, Emma C., Chou, Yi Ling, Coleman, Jonathan R.I., Thornton, Laura M., Walters, Raymond K., Yilmaz, Zeynep, Baker, Jessica H., Hübel, Christopher, Gordon, Scott, Medland, Sarah E., Watson, Hunna J., Gaspar, Héléna A., Bryois, Julien, Hinney, Anke, Leppä, Virpi M., Mattheisen, Manuel, Ripke, Stephan, Yao, Shuyang, Giusti-Rodríguez, Paola, Hanscombe, Ken B., Adan, Roger A.H., Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole A., Berrettini, Wade H., Boehm, Ilka, Boni, Claudette, Boraska Perica, Vesna, Buehren, Katharina, Burghardt, Roland, Cassina, Matteo, Cichon, Sven, Clementi, Maurizio, Cone, Roger D., Courtet, Philippe, Crow, Scott, Crowley, James J., Danner, Unna N., Davis, Oliver S.P., de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E., Dick, Danielle M., Dikeos, Dimitris, Dina, Christian, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Duncan, Laramie E., Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M., Fischer, Krista, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J., Forzan, Monica, Franklin, Christopher S., Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos Mayora, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske G., Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Huckins, Laura M., Hudson, James I., Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J.H., Kennedy, James L., Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl Ri, Klump, Kelly L., Knudsen, Gun Peggy S., La Via, Maria C., Le Hellard, Stephanie, Levitan, Robert D., Li, Dong, Lilenfeld, Lisa, Lin, Bochao Danae, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre J., Maj, Mario, Mannik, Katrin, Marsal, Sara, Marshall, Christian R., Mattingsdal, Morten, McDevitt, Sara, McGuffin, Peter, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen, Monteleone, Alessio Maria, Monteleone, Palmiero, Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, O'Toole, Julie K., Ophoff, Roel A., Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Pinto, Dalila, Rabionet, Raquel, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W., Schmidt, Ulrike, Schork, Nicholas J., Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P. Eline, Slof-Op't Landt, Margarita C.T., Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Szatkiewicz, Jin P., Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A., van Furth, Eric F., Wagner, Gudrun, Walton, Esther, Widen, Elisabeth, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W., Boden, Joseph M., Brandt, Harry, Crawford, Steven, Halmi, Katherine A., Horwood, L. John, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Mitchell, James, Olsen, Catherine M., Pearson, John F., Pedersen, Nancy L., Strober, Michael, Werge, Thomas, Whiteman, David C., Woodside, D. Blake, Grove, Jakob, Henders, Anjali K., Larsen, Janne T., Parker, Richard, Petersen, Liselotte V., Jordan, Jennifer, Kennedy, Martin A., Birgegård, Andreas, Lichtenstein, Paul, Norring, Claes, Landén, Mikael, Mortensen, Preben Bo, Polimanti, Renato, McClintick, Jeanette N., Adkins, Amy E., Aliev, Fazil, Bacanu, Silviu Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna M., Bigdeli, Tim B., Chen, Li Shiun, Clarke, Toni Kim, Degenhardt, Franziska, Docherty, Anna R., Edwards, Alexis C., Foo, Jerome C., Fox, Louis, Frank, Josef, Hack, Laura M., Hartmann, Annette M., Hartz, Sarah M., Heilmann-Heimbach, Stefanie, Hodgkinson, Colin, Hoffmann, Per, Hottenga, Jouke Jan, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion S., Mbarek, Hamdi, McIntosh, Andrew M., McQueen, Matthew B., Meyers, Jacquelyn L., Milaneschi, Yuri, Palviainen, Teemu, Peterson, Roseann E., Ryu, Euijung, Saccone, Nancy L., Salvatore, Jessica E., Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen Chyong, Webb, Bradley T., Wedow, Robbee, Wetherill, Leah, Wills, Amanda G., Zhou, Hang, Boardman, Jason D., Chen, Danfeng, Choi, Doo Sup, Copeland, William E., Culverhouse, Robert C., Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W., Frye, Mark A., Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Koller, Gabriele, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T., Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison D., Nurnberger, John I., Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D., Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc A., Soyka, Michael, Treutlein, Jens, Witt, Stephanie H., Wodarz, Norbert, Zill, Peter, Adkins, Daniel E., Boomsma, Dorret I., Bierut, Laura J., Brown, Sandra A., Bucholz, Kathleen K., Costello, E. Jane, de Wit, Harriet, Diazgranados, Nancy, Eriksson, Johan G., Farrer, Lindsay A., Foroud, Tatiana M., Gillespie, Nathan A., Goate, Alison M., Goldman, David, Grucza, Richard A., Hancock, Dana B., Harris, Kathleen Mullan, Hesselbrock, Victor, Hewitt, John K., Hopfer, Christian J., Iacono, William G., Johnson, Eric O., Karpyak, Victor M., Kendler, Kenneth S., Kranzler, Henry R., Krauter, Kenneth, Lind, Penelope A., McGue, Matt, MacKillop, James, Madden, Pamela A.F., Maes, Hermine H., Magnusson, Patrik K.E., Nelson, Elliot C., Nöthen, Markus M., Palmer, Abraham A., Penninx, Brenda W.J.H., Porjesz, Bernice, Rice, John P., Rietschel, Marcella, Riley, Brien P., Rose, Richard J., Shen, Pei Hong, Silberg, Judy, Stallings, Michael C., Tarter, Ralph E., Vanyukov, Michael M., Vrieze, Scott, Wall, Tamara L., Whitfield, John B., Zhao, Hongyu, Neale, Benjamin M., Wade, Tracey D., Heath, Andrew C., Montgomery, Grant W., Martin, Nicholas G., Sullivan, Patrick F., Kaprio, Jaakko, Breen, Gerome, Gelernter, Joel, Edenberg, Howard J., Bulik, Cynthia M., and Agrawal, Arpana
Abstract: Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotyp
Published: 2020

41. A large-scale genome-wide association study meta-analysis of cannabis use disorder

Author: Johnson, Emma C., Demontis, Ditte, Thorgeirsson, Thorgeir E., Walters, Raymond K., Polimanti, Renato, Hatoum, Alexander S., Sanchez-Roige, Sandra, Paul, Sarah E., Wendt, Frank R., Clarke, Toni Kim, Lai, Dongbing, Reginsson, Gunnar W., Zhou, Hang, He, June, Baranger, David A.A., Gudbjartsson, Daniel F., Wedow, Robbee, Adkins, Daniel E., Adkins, Amy E., Alexander, Jeffry, Bacanu, Silviu Alin, Bigdeli, Tim B., Boden, Joseph, Brown, Sandra A., Bucholz, Kathleen K., Bybjerg-Grauholm, Jonas, Corley, Robin P., Degenhardt, Louisa, Dick, Danielle M., Domingue, Benjamin W., Fox, Louis, Goate, Alison M., Gordon, Scott D., Hack, Laura M., Hancock, Dana B., Hartz, Sarah M., Hickie, Ian B., Hougaard, David M., Krauter, Kenneth, Lind, Penelope A., McClintick, Jeanette N., McQueen, Matthew B., Meyers, Jacquelyn L., Montgomery, Grant W., Mors, Ole, Mortensen, Preben B., Nordentoft, Merete, Pearson, John F., Peterson, Roseann E., Werge, Thomas, Johnson, Emma C., Demontis, Ditte, Thorgeirsson, Thorgeir E., Walters, Raymond K., Polimanti, Renato, Hatoum, Alexander S., Sanchez-Roige, Sandra, Paul, Sarah E., Wendt, Frank R., Clarke, Toni Kim, Lai, Dongbing, Reginsson, Gunnar W., Zhou, Hang, He, June, Baranger, David A.A., Gudbjartsson, Daniel F., Wedow, Robbee, Adkins, Daniel E., Adkins, Amy E., Alexander, Jeffry, Bacanu, Silviu Alin, Bigdeli, Tim B., Boden, Joseph, Brown, Sandra A., Bucholz, Kathleen K., Bybjerg-Grauholm, Jonas, Corley, Robin P., Degenhardt, Louisa, Dick, Danielle M., Domingue, Benjamin W., Fox, Louis, Goate, Alison M., Gordon, Scott D., Hack, Laura M., Hancock, Dana B., Hartz, Sarah M., Hickie, Ian B., Hougaard, David M., Krauter, Kenneth, Lind, Penelope A., McClintick, Jeanette N., McQueen, Matthew B., Meyers, Jacquelyn L., Montgomery, Grant W., Mors, Ole, Mortensen, Preben B., Nordentoft, Merete, Pearson, John F., Peterson, Roseann E., and Werge, Thomas
Abstract: Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10−9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10−9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10−21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with oth
Published: 2020

42. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author: Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, de Boer, Rudolf A, de Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela A F, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D P, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renstrom, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, van der Leij, Andries R, van der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin N A, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, van der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, Howson, Joanna M M, Erzurumluoglu, A. Mesut, Liu, Mengzhen, Jackson, Victoria E., Barnes, Daniel R., Datta, Gargi, Melbourne, Carl A., Young, Robin, Batini, Chiara, Surendran, Praveen, Jiang, Tao, Adnan, Sheikh Daud, Afaq, Saima, Agrawal, Arpana, Altmaier, Elisabeth, Antoniou, Antonis C., Asselbergs, Folkert W., Baumbach, Clemens, Bierut, Laura, Bertelsen, Sarah, Boehnke, Michael, Bots, Michiel L, Brazel, David M, Chambers, John C, Chang-Claude, Jenny, Chen, Chu, Corley, Janie, Chou, Yi-Ling, David, Sean P, de Boer, Rudolf A, de Leeuw, Christiaan A, Dennis, Joe G, Dominiczak, Anna F, Dunning, Alison M, Easton, Douglas F, Eaton, Charles, Elliott, Paul, Evangelou, Evangelos, Faul, Jessica D, Foroud, Tatiana, Goate, Alison, Gong, Jian, Grabe, Hans J, Haessler, Jeff, Haiman, Christopher, Hallmans, Göran, Hammerschlag, Anke R, Harris, Sarah E, Hattersley, Andrew, Heath, Andrew, Hsu, Chris, Iacono, William G, Kanoni, Stavroula, Kapoor, Manav, Kaprio, Jaakko, Kardia, Sharon L, Karpe, Fredrik, Kontto, Jukka, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Laakso, Markku, Lai, Dongbing, Langenberg, Claudia, Le, Nhung, Lettre, Guillaume, Loukola, Anu, Luan, Jian'an, Madden, Pamela A F, Mangino, Massimo, Marioni, Riccardo E, Marouli, Eirini, Marten, Jonathan, Martin, Nicholas G, McGue, Matt, Michailidou, Kyriaki, Mihailov, Evelin, Moayyeri, Alireza, Moitry, Marie, Müller-Nurasyid, Martina, Naheed, Aliya, Nauck, Matthias, Neville, Matthew J, Nielsen, Sune Fallgaard, North, Kari, Perola, Markus, Pharoah, Paul D P, Pistis, Giorgio, Polderman, Tinca J, Posthuma, Danielle, Poulter, Neil, Qaiser, Beenish, Rasheed, Asif, Reiner, Alex, Renstrom, Frida, Rice, John, Rohde, Rebecca, Rolandsson, Olov, Samani, Nilesh J, Samuel, Maria, Schlessinger, David, Scholte, Steven H, Scott, Robert A, Sever, Peter, Shao, Yaming, Shrine, Nick, Smith, Jennifer A, Starr, John M, Stirrups, Kathleen, Stram, Danielle, Stringham, Heather M, Tachmazidou, Ioanna, Tardif, Jean-Claude, Thompson, Deborah J, Tindle, Hilary A, Tragante, Vinicius, Trompet, Stella, Turcot, Valerie, Tyrrell, Jessica, Vaartjes, Ilonca, van der Leij, Andries R, van der Meer, Peter, Varga, Tibor V, Verweij, Niek, Völzke, Henry, Wareham, Nicholas J, Warren, Helen R, Weir, David R, Weiss, Stefan, Wetherill, Leah, Yaghootkar, Hanieh, Yavas, Ersin, Jiang, Yu, Chen, Fang, Zhan, Xiaowei, Zhang, Weihua, Zhao, Wei, Zhou, Kaixin, Amouyel, Philippe, Blankenberg, Stefan, Caulfield, Mark J, Chowdhury, Rajiv, Cucca, Francesco, Deary, Ian J, Deloukas, Panos, Di Angelantonio, Emanuele, Ferrario, Marco, Ferrières, Jean, Franks, Paul W, Frayling, Tim M, Frossard, Philippe, Hall, Ian P, Hayward, Caroline, Jansson, Jan-Håkan, Jukema, J Wouter, Kee, Frank, Männistö, Satu, Metspalu, Andres, Munroe, Patricia B, Nordestgaard, Børge Grønne, Palmer, Colin N A, Salomaa, Veikko, Sattar, Naveed, Spector, Timothy, Strachan, David Peter, van der Harst, Pim, Zeggini, Eleftheria, Saleheen, Danish, Butterworth, Adam S, Wain, Louise V, Abecasis, Goncalo R, Danesh, John, Tobin, Martin D, Vrieze, Scott, Liu, Dajiang J, and Howson, Joanna M M
Abstract: Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
Published: 2020
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43. Exome-chip association analysis of intracranial aneurysms

Author: Onderzoek Precision medicine, Cardiovasculaire Epi Team 5, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Neurologie, Brain, CMM Groep Kaaij, ZL Cerebrovasculaire Ziekten Medisch, van 't Hof, Femke N G, Lai, Dongbing, van Setten, Jessica, Bots, Michiel L, Vaartjes, Ilonca, Broderick, Joseph, Woo, Daniel, Foroud, Tatiana, Rinkel, Gabriel J E, de Bakker, Paul I W, Ruigrok, Ynte M, Onderzoek Precision medicine, Cardiovasculaire Epi Team 5, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Neurologie, Brain, CMM Groep Kaaij, ZL Cerebrovasculaire Ziekten Medisch, van 't Hof, Femke N G, Lai, Dongbing, van Setten, Jessica, Bots, Michiel L, Vaartjes, Ilonca, Broderick, Joseph, Woo, Daniel, Foroud, Tatiana, Rinkel, Gabriel J E, de Bakker, Paul I W, and Ruigrok, Ynte M
Published: 2020

44. Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

Author: Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valérie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Barnes, Daniel R., Bertelsen, Sarah, Chou, Yi-Ling, Erzurumluoglu, A. Mesut, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Melbourne, Carl A., Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Zhao, Wei, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Howson, Joanna M. M., Kardia, Sharon L. R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, McGue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Tobin, Martin D., Weir, David R., Kaprio, Jaakko, Abecasis, Gonçalo R., Liu, Dajiang J., Vrieze, Scott, Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valérie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Barnes, Daniel R., Bertelsen, Sarah, Chou, Yi-Ling, Erzurumluoglu, A. Mesut, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Melbourne, Carl A., Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Zhao, Wei, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Howson, Joanna M. M., Kardia, Sharon L. R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, McGue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Tobin, Martin D., Weir, David R., Kaprio, Jaakko, Abecasis, Gonçalo R., Liu, Dajiang J., and Vrieze, Scott
Abstract: BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior., Group Author(s): CHD Exome Consortium; Consortium Genetics Smoking; EPIC-CVD Consortium; Understanding Soc Sci Grp
Published: 2019
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45. ERRATUM: Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Author: Wetherill, Leah, Wetherill, Leah, Lai, Dongbing, Johnson, Emma C, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K, Dick, Danielle M, Hariri, Ahmad R, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L, Nurnberger, John I, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Porjesz, Bernice, Goate, Alison M, Edenberg, Howard J, Foroud, Tatiana, Bogdan, Ryan, Agrawal, Arpana, Wetherill, Leah, Wetherill, Leah, Lai, Dongbing, Johnson, Emma C, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K, Dick, Danielle M, Hariri, Ahmad R, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L, Nurnberger, John I, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Porjesz, Bernice, Goate, Alison M, Edenberg, Howard J, Foroud, Tatiana, Bogdan, Ryan, and Agrawal, Arpana
Published: 2019

46. Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Author: Wetherill, Leah, Wetherill, Leah, Lai, Dongbing, Johnson, Emma C, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K, Dick, Danielle M, Hariri, Ahmad R, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L, Nurnberger, John I, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Porjesz, Bernice, Goate, Alison M, Edenberg, Howard J, Foroud, Tatiana, Bogdan, Ryan, Agrawal, Arpana, Wetherill, Leah, Wetherill, Leah, Lai, Dongbing, Johnson, Emma C, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K, Dick, Danielle M, Hariri, Ahmad R, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L, Nurnberger, John I, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Porjesz, Bernice, Goate, Alison M, Edenberg, Howard J, Foroud, Tatiana, Bogdan, Ryan, and Agrawal, Arpana
Abstract: Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.
Published: 2019

47. ERRATUM: Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Author: Wetherill, Leah, Wetherill, Leah, Lai, Dongbing, Johnson, Emma C, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K, Dick, Danielle M, Hariri, Ahmad R, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L, Nurnberger, John I, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Porjesz, Bernice, Goate, Alison M, Edenberg, Howard J, Foroud, Tatiana, Bogdan, Ryan, Agrawal, Arpana, Wetherill, Leah, Wetherill, Leah, Lai, Dongbing, Johnson, Emma C, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K, Dick, Danielle M, Hariri, Ahmad R, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L, Nurnberger, John I, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Porjesz, Bernice, Goate, Alison M, Edenberg, Howard J, Foroud, Tatiana, Bogdan, Ryan, and Agrawal, Arpana
Published: 2019

48. Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Author: Wetherill, Leah, Wetherill, Leah, Lai, Dongbing, Johnson, Emma C, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K, Dick, Danielle M, Hariri, Ahmad R, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L, Nurnberger, John I, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Porjesz, Bernice, Goate, Alison M, Edenberg, Howard J, Foroud, Tatiana, Bogdan, Ryan, Agrawal, Arpana, Wetherill, Leah, Wetherill, Leah, Lai, Dongbing, Johnson, Emma C, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen K, Dick, Danielle M, Hariri, Ahmad R, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn L, Nurnberger, John I, Schuckit, Marc, Scott, Denise M, Taylor, Robert E, Tischfield, Jay, Porjesz, Bernice, Goate, Alison M, Edenberg, Howard J, Foroud, Tatiana, Bogdan, Ryan, and Agrawal, Arpana
Abstract: Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.
Published: 2019

49. Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Author: Wetherill, Leah, Wetherill, Leah, Lai, Dongbing, Johnson, Emma, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen, Dick, Danielle, Hariri, Ahmad, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn, Nurnberger, John, Scott, Denise, Taylor, Robert, Tischfield, Jay, Porjesz, Bernice, Goate, Alison, Edenberg, Howard, Foroud, Tatiana, Bogdan, Ryan, Agrawal, Arpana, Schuckit, Marc, Wetherill, Leah, Wetherill, Leah, Lai, Dongbing, Johnson, Emma, Anokhin, Andrey, Bauer, Lance, Bucholz, Kathleen, Dick, Danielle, Hariri, Ahmad, Hesselbrock, Victor, Kamarajan, Chella, Kramer, John, Kuperman, Samuel, Meyers, Jacquelyn, Nurnberger, John, Scott, Denise, Taylor, Robert, Tischfield, Jay, Porjesz, Bernice, Goate, Alison, Edenberg, Howard, Foroud, Tatiana, Bogdan, Ryan, Agrawal, Arpana, and Schuckit, Marc
Abstract: Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.
Published: 2019

50. Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

Author: Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valerie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Barnes, Daniel R., Bertelsen, Sarah, Chou, Yi-Ling, Erzurumluoglu, A. Mesut, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Melbourne, Carl A., Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Zhao, Wei, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Howson, Joanna M. M., Kardia, Sharon L. R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, Mcgue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Tobin, Martin D., Weir, David R., Kaprio, Jaakko, Abecasis, Goncalo R., Liu, Dajiang J., Vrieze, Scott, Surendran, Praveen, Young, Robin, Nielsen, Sune Fallgaard, Rasheed, Asif, Samuel, Maria, Kontto, Jukka, Perola, Markus, Caslake, Muriel, de Craen, Anton J. M., Trompet, Stella, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F., Hoek, Maarten, Vogt, Thomas, Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Alam, Dewan S., Majumder, Abdulla al Shafi, Di Ange-Lantonio, Emanuele, Chowdhury, Rajiv, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrieres, Jean, Kee, Frank, Kuulasmaa, Kari, Mueller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, Frossard, Philippe, Nordestgaard, Borge Gronne, Saleheen, Danish, Danesh, John, Butterworth, Adam S., Jackson, Victoria E., Varga, Tibor V., Warren, Helen R., Tragante, Vinicius, Tachmazidou, Ioanna, Harris, Sarah E., Evangelou, Evangelos, Marten, Jonathan, Zhang, Weihua, Altmaier, Elisabeth, Luan, Jian'an, Langenberg, Claudia, Scott, Robert A., Yaghootkar, Hanieh, Stirrups, Kathleen, Kanoni, Stavroula, Marouli, Eirini, Karpe, Fredrik, Dominiczak, Anna F., Sever, Peter, Poulter, Neil, Rolandsson, Olov, Baumbach, Clemens, Afaq, Saima, Chambers, John C., Kooner, Jaspal S., Wareham, Nicholas J., Renstrom, Frida, Hallmans, Goran, Marioni, Riccardo E., Corley, Janie, Starr, John M., Verweij, Niek, de Boer, Rudolf A., van der Meer, Peter, Yavas, Ersin, Vaartjes, Ilonca, Bots, Michiel L., Asselbergs, Folkert W., Grabe, Hans J., Volzke, Henry, Nauck, Matthias, Weiss, Stefan, Pharoah, Paul D. P., Dunning, Alison M., Dennis, Joe G., Thompson, Deborah J., Michailidou, Kyriaki, Easton, Douglas F., Antoniou, Antonis C., Tyrrell, Jessica, Mihailov, Evelin, Samani, Nilesh J., Zhou, Kaixin, Neville, Matthew J., Metspalu, Andres, Palmer, Colin N. A., Hall, Ian P., Strachan, David P., Deary, Ian J., Frayling, Tim M., Hayward, Caroline, van der Harst, Pim, Zeggini, Eleftheria, Munroe, Patricia B., Jansson, Jan-Hakan, Franks, Paul W., Deloukas, Panos, Caulfield, Mark J., Wain, Louise V., Brazel, David M., Jiang, Yu, Hughey, Jordan M., Turcot, Valerie, Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Weissenkampen, J. Dylan, Liu, MengZhen, Barnes, Daniel R., Bertelsen, Sarah, Chou, Yi-Ling, Erzurumluoglu, A. Mesut, Faul, Jessica D., Haessler, Jeff, Hammerschlag, Anke R., Hsu, Chris, Kapoor, Manav, Lai, Dongbing, Le, Nhung, de Leeuw, Christiaan A., Loukola, Anu, Mangino, Massimo, Melbourne, Carl A., Pistis, Giorgio, Qaiser, Beenish, Rohde, Rebecca, Shao, Yaming, Stringham, Heather, Wetherill, Leah, Zhao, Wei, Agrawal, Arpana, Bierut, Laura, Chen, Chu, Eaton, Charles B., Goate, Alison, Haiman, Christopher, Heath, Andrew, Iacono, William G., Martin, Nicholas G., Polderman, Tinca J., Reiner, Alex, Rice, John, Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Tardif, Jean-Claude, Tindle, Hilary A., van der Leij, Andries R., Boehnke, Michael, Chang-Claude, Jenny, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Howson, Joanna M. M., Kardia, Sharon L. R., Kooperberg, Charles, Laakso, Markku, Lettre, Guillaume, Madden, Pamela, Mcgue, Matt, North, Kari, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Tobin, Martin D., Weir, David R., Kaprio, Jaakko, Abecasis, Goncalo R., Liu, Dajiang J., Vrieze, Scott, Surendran, Praveen, Young, Robin, Nielsen, Sune Fallgaard, Rasheed, Asif, Samuel, Maria, Kontto, Jukka, Perola, Markus, Caslake, Muriel, de Craen, Anton J. M., Trompet, Stella, Uria-Nickelsen, Maria, Malarstig, Anders, Reily, Dermot F., Hoek, Maarten, Vogt, Thomas, Jukema, J. Wouter, Sattar, Naveed, Ford, Ian, Packard, Chris J., Alam, Dewan S., Majumder, Abdulla al Shafi, Di Ange-Lantonio, Emanuele, Chowdhury, Rajiv, Amouyel, Philippe, Arveiler, Dominique, Blankenberg, Stefan, Ferrieres, Jean, Kee, Frank, Kuulasmaa, Kari, Mueller-Nurasyid, Martina, Veronesi, Giovanni, Virtamo, Jarmo, Frossard, Philippe, Nordestgaard, Borge Gronne, Saleheen, Danish, Danesh, John, Butterworth, Adam S., Jackson, Victoria E., Varga, Tibor V., Warren, Helen R., Tragante, Vinicius, Tachmazidou, Ioanna, Harris, Sarah E., Evangelou, Evangelos, Marten, Jonathan, Zhang, Weihua, Altmaier, Elisabeth, Luan, Jian'an, Langenberg, Claudia, Scott, Robert A., Yaghootkar, Hanieh, Stirrups, Kathleen, Kanoni, Stavroula, Marouli, Eirini, Karpe, Fredrik, Dominiczak, Anna F., Sever, Peter, Poulter, Neil, Rolandsson, Olov, Baumbach, Clemens, Afaq, Saima, Chambers, John C., Kooner, Jaspal S., Wareham, Nicholas J., Renstrom, Frida, Hallmans, Goran, Marioni, Riccardo E., Corley, Janie, Starr, John M., Verweij, Niek, de Boer, Rudolf A., van der Meer, Peter, Yavas, Ersin, Vaartjes, Ilonca, Bots, Michiel L., Asselbergs, Folkert W., Grabe, Hans J., Volzke, Henry, Nauck, Matthias, Weiss, Stefan, Pharoah, Paul D. P., Dunning, Alison M., Dennis, Joe G., Thompson, Deborah J., Michailidou, Kyriaki, Easton, Douglas F., Antoniou, Antonis C., Tyrrell, Jessica, Mihailov, Evelin, Samani, Nilesh J., Zhou, Kaixin, Neville, Matthew J., Metspalu, Andres, Palmer, Colin N. A., Hall, Ian P., Strachan, David P., Deary, Ian J., Frayling, Tim M., Hayward, Caroline, van der Harst, Pim, Zeggini, Eleftheria, Munroe, Patricia B., Jansson, Jan-Hakan, Franks, Paul W., Deloukas, Panos, Caulfield, Mark J., and Wain, Louise V.
Published: 2019

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