title: Association of Superoxide Dismutase 2 (SOD2) Genotype with Gray Matter Volume Shrinkage in Chronic Alcohol Users: Replication and Further Evaluation of an Addiction Gene Panel.
abstract: BACKGROUND
  Reduction in brain volume, especially gray matter volume, has been shown to be one of the many deleterious effects of prolonged alcohol consumption. High variance in the degree of gray matter tissue shrinkage among alcohol-dependent individuals and a previous neuroimaging genetics report suggest the involvement of environmental and/or genetic factors, such as superoxide dismutase 2 (SOD2). Identification of such underlying factors will help in the clinical management of alcohol dependence.
  
  
  METHODS
  We analyzed quantitative magnetic resonance imaging and genotype data from 103 alcohol users, including both light drinkers and treatment-seeking alcohol-dependent individuals. Genotyping was performed using a custom gene array that included genes selected from 8 pathways relevant to chronic alcohol-related brain volume loss.
  
  
  RESULTS
  We replicated a significant association of a functional SOD2 single nucleotide polymorphism with normalized gray matter volume, which had been reported previously in an independent smaller sample of alcohol-dependent individuals. The SOD2-related genetic protection was observed only at the cohort's lower drinking range. Additional associations between normalized gray matter volume and other candidate genes such as alcohol dehydrogenase gene cluster (ADH), GCLC, NOS3, and SYT1 were observed across the entire sample but did not survive corrections for multiple comparisons.
  
  
  CONCLUSIONS
  Converging independent evidence for a SOD2 gene association with gray matter volume shrinkage in chronic alcohol users suggests that SOD2 genetic variants predict differential brain volume loss mediated by free radicals. This study also provides the first catalog of genetic variations relevant to gray matter loss in chronic alcohol users. The identified gene-brain structure relationships are functionally pertinent and merit replication.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland (Drs Gitik, Srivastava, and Hodgkinson, Ms Shen, and Dr Goldman); Department of Radiology and Biomedical Imaging, University of California, San Francisco, California (Dr Meyerhoff); Center for Imaging of Neurodegenerative Diseases, Veterans Administration Medical Center, San Francisco, California (Dr Meyerhoff).Current address (V.S.): Molecular Genetic Technology Program, School of Health Professions, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
authors.forename: Miri
authors.initials: M
authors.lastname: Gitik
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland (Drs Gitik, Srivastava, and Hodgkinson, Ms Shen, and Dr Goldman); Department of Radiology and Biomedical Imaging, University of California, San Francisco, California (Dr Meyerhoff); Center for Imaging of Neurodegenerative Diseases, Veterans Administration Medical Center, San Francisco, California (Dr Meyerhoff).Current address (V.S.): Molecular Genetic Technology Program, School of Health Professions, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
authors.forename: Vibhuti
authors.initials: V
authors.lastname: Srivastava
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland (Drs Gitik, Srivastava, and Hodgkinson, Ms Shen, and Dr Goldman); Department of Radiology and Biomedical Imaging, University of California, San Francisco, California (Dr Meyerhoff); Center for Imaging of Neurodegenerative Diseases, Veterans Administration Medical Center, San Francisco, California (Dr Meyerhoff).Current address (V.S.): Molecular Genetic Technology Program, School of Health Professions, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Hodgkinson
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland (Drs Gitik, Srivastava, and Hodgkinson, Ms Shen, and Dr Goldman); Department of Radiology and Biomedical Imaging, University of California, San Francisco, California (Dr Meyerhoff); Center for Imaging of Neurodegenerative Diseases, Veterans Administration Medical Center, San Francisco, California (Dr Meyerhoff).Current address (V.S.): Molecular Genetic Technology Program, School of Health Professions, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
authors.forename: Pei-Hong
authors.initials: PH
authors.lastname: Shen
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland (Drs Gitik, Srivastava, and Hodgkinson, Ms Shen, and Dr Goldman); Department of Radiology and Biomedical Imaging, University of California, San Francisco, California (Dr Meyerhoff); Center for Imaging of Neurodegenerative Diseases, Veterans Administration Medical Center, San Francisco, California (Dr Meyerhoff).Current address (V.S.): Molecular Genetic Technology Program, School of Health Professions, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland (Drs Gitik, Srivastava, and Hodgkinson, Ms Shen, and Dr Goldman); Department of Radiology and Biomedical Imaging, University of California, San Francisco, California (Dr Meyerhoff); Center for Imaging of Neurodegenerative Diseases, Veterans Administration Medical Center, San Francisco, California (Dr Meyerhoff).Current address (V.S.): Molecular Genetic Technology Program, School of Health Professions, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. dieter.meyerhoff@ucsf.edu.
authors.forename: Dieter J
authors.initials: DJ
authors.lastname: Meyerhoff
keywords: Alcohol use disorder; genetics; gray matter volume; neuroimaging; superoxide dismutase 2 (SOD2)