CREB-BDNF pathway influences alcohol cue-elicited activation in drinkers.
Alcohol use disorder (AUD) is suggested to have polygenic risk factors and also exhibits neurological complications, strongly encouraging a translational study to explore the associations between aggregates of genetic variants and brain function alterations related to alcohol use. In this study, we used a semiblind multivariate approach, parallel independent component analysis with multiple references (pICA-MR) to investigate relationships of genome-wide single nucleotide polymorphisms with alcohol cue-elicited brain activations in 315 heavy drinkers, where pICA-MR assesses multiple reference genes for their architecture and functional influences on neurobiological conditions. The genetic component derived from the cAMP-response element-binding protein and -brain derived neurotrophic factor (CREB-BDNF) pathway reference was significantly associated (r = -0.38, P = 3.98 × 10(-12) ) with an imaging component reflecting hyperactivation in precuneus, superior parietal lobule, and posterior cingulate for drinkers with more severe alcohol dependence symptoms. The highlighted brain regions participate in many cognitive processes and have been robustly implicated in craving-related studies. The genetic factor highlighted the CREB and BDNF references, as well as other genes including GRM5, GRM7, GRID1, GRIN2A, PRKCA, and PRKCB. Ingenuity Pathway Analysis indicated that the genetic component was enriched in synaptic plasticity, GABA, and protein kinase A signaling. Collectively, our findings suggest that genetic variations in various neural plasticity and signaling pathways partially explain the variance of precuneus reactivity to alcohol cues which appears to be associated with AUD severity.
The Mind Research Network, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico.
Jiayu
J
Chen
The Mind Research Network, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico.|Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, Colorado.
Kent E
KE
Hutchison
The Mind Research Network, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico.|Department of Electrical Engineering, University of New Mexico, Albuquerque, New Mexico.
Vince D
VD
Calhoun
The Mind Research Network, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico.
Eric D
ED
Claus
The Mind Research Network, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico.|Psychology Department and Neuroscience Institute, Georgia State University, Atlanta, Georgia.
Jessica A
JA
Turner
The Mind Research Network, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico.|Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
Jing
J
Sui
The Mind Research Network, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico.|Department of Electrical Engineering, University of New Mexico, Albuquerque, New Mexico.
Jingyu
J
Liu
D000328:Adult; D019973:Alcohol-Related Disorders / Q000235:genetics* / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003463:Cues; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D055697:Taste Perception / Q000187:drug effects / Q000502:physiology*; D055815:Young Adult
D019208:Brain-Derived Neurotrophic Factor; C115163:CREB1 protein, human; D002492:Central Nervous System Depressants; D017362:Cyclic AMP Response Element-Binding Protein; D000431:Ethanol; C579455:BDNF protein, human
alcohol use disorder; brain derived neurotrophic factor; cAMP-response element-binding; functional magnetic resonance imaging; parallel independent component analysis with multiple references; precuneus; single nucleotide polymorphism