title: Genome-wide association study of body mass index in subjects with alcohol dependence.
abstract: Outcomes related to disordered metabolism are common in alcohol dependence (AD). To investigate alterations in the regulation of body mass that occur in the context of AD, we performed a genome-wide association study (GWAS) of body mass index (BMI) in African Americans (AAs) and European Americans (EAs) with AD. Subjects were recruited for genetic studies of AD or drug dependence and evaluated using the Semi-structured Assessment for Drug Dependence and Alcoholism. We investigated a total of 2587 AAs and 2959 EAs with DSM-IV AD diagnosis. In the stage 1 sample (N = 4137), we observed three genome-wide significant (GWS) single-nucleotide polymorphism associations, rs200889048 (P = 8.98 * 10-12) and rs12490016 (P = 1.44 * 10-8) in EAs and rs1630623 (P = 5.14 * 10-9) in AAs and EAs meta-analyzed. In the stage 2 sample (N = 1409), we replicated 278, 253 and 168 of the stage 1 suggestive loci (P < 5*10-4) in AAs, EAs, and AAs and EAs meta-analyzed, respectively. A meta-analysis of stage 1 and stage 2 samples (N = 5546) identified two additional GWS signals: rs28562191 in EAs (P = 4.46 * 10-8) and rs56950471 in AAs (P = 1.57 * 10-9). Three of the GWS loci identified (rs200889048, rs12490016 and rs1630623) were not previously reported by GWAS of BMI in the general population, and two of them raise interesting hypotheses: rs12490016-a regulatory variant located within LINC00880, where there are other GWAS-identified variants associated with birth size, adiposity in newborns and bulimia symptoms, which also interact with social stress in relation to birth size; rs1630623-a regulatory variant related to ALDH1A1, a gene involved in alcohol metabolism and adipocyte plasticity. These loci offer molecular insights regarding the regulatory mechanisms of body mass in the context of AD.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, CT, USA.
authors.forename: Renato
authors.initials: R
authors.lastname: Polimanti
authors.affiliation: Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, CT, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Medical Scientist Training Program and Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Smith
authors.affiliation: Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA.|Department of Genetics, Yale University School of Medicine, New Haven CT, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.|Department of Neurology, Boston University School of Medicine, Boston, MA, USA.|Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA.|Department of Genetics and Genomics, Boston University School of Medicine, Boston, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.|Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: Department of Psychiatry, University of Pennsylvania School of Medicine, VISN 4 MIRECC, Philadelphia VAMC, Philadelphia, PA, USA.
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, CT, USA.|Department of Genetics, Yale University School of Medicine, New Haven CT, USA.|Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics; D000262:Adenylyl Cyclases / Q000235:genetics; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000437:Alcoholism / Q000150:complications*; D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000235:genetics; D015992:Body Mass Index; D015815:Cell Adhesion Molecules / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D050956:HSP40 Heat-Shock Proteins; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D009765:Obesity / Q000150:complications / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000235:genetics; D050697:Retinal Dehydrogenase; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000235:genetics
chemical_list: C556123:CADM2 protein, human; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D062085:RNA, Long Noncoding; C443860:SEC16B protein, human; C530715:TMEM18 protein, human; D014157:Transcription Factors; C082354:neurexin IIIalpha; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D017766:Acid Anhydride Hydrolases; C000589559:DNAJC27 protein, human; C116368:diphosphoinositol polyphosphate phosphohydrolase; D020691:rab GTP-Binding Proteins; D000262:Adenylyl Cyclases; C421784:adenylate cyclase 3
keywords: Alcohol addiction; GWAS; ancestry; complex traits; genetics; metabolic processes