TY - JOUR
T1 - Genome-wide association study of theta band event-related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence
AU - Zlojutro, Mark
AU - Manz, Niklas
AU - Rangaswamy, Madhavi
AU - Xuei, Xiaoling
AU - Flury-Wetherill, Leah
AU - Koller, Daniel
AU - Bierut, Laura J.
AU - Goate, Alison
AU - Hesselbrock, Victor
AU - Kuperman, Samuel
AU - Nurnberger, John
AU - Rice, John P.
AU - Schuckit, Marc A.
AU - Foroud, Tatiana
AU - Edenberg, Howard J.
AU - Porjesz, Bernice
AU - Almasy, Laura
PY - 2011/1
Y1 - 2011/1
N2 - Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome-wide association study (GWAS) of an ERO endophenotype-frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty-two SNPs of the Illumina HumanHap 1M microarray were selected from the theta ERO GWAS for replication in family-based samples (N=1,095), with four markers revealing nominally significant association. The most significant marker from the two-stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher's combined P=3.68×10-6). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P=1.53×10-4), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM-IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case-controls (P=0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case-control and family-based samples (P=0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders.
AB - Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome-wide association study (GWAS) of an ERO endophenotype-frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty-two SNPs of the Illumina HumanHap 1M microarray were selected from the theta ERO GWAS for replication in family-based samples (N=1,095), with four markers revealing nominally significant association. The most significant marker from the two-stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher's combined P=3.68×10-6). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P=1.53×10-4), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM-IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case-controls (P=0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case-control and family-based samples (P=0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders.
KW - Alcohol dependence
KW - Event-related oscillation (ERO)
KW - Genome-wide association study (GWAS)
KW - Serotonin receptor (5-HT)
KW - Serotonin receptor gene (HTR7)
UR - http://www.scopus.com/inward/record.url?scp=79953655029&partnerID=8YFLogxK
U2 - 10.1002/ajmg.b.31136
DO - 10.1002/ajmg.b.31136
M3 - Article
C2 - 21184583
AN - SCOPUS:79953655029
SN - 1552-4841
VL - 156
SP - 44
EP - 58
JO - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
JF - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
IS - 1
ER -