Allele-Specific Methylation of SPDEF: A Novel Moderator of Psychosocial Stress and Substance Abuse
Abstract
Objective:
Methods:
Results:
Conclusions:
Methods
Participants
Questionnaire and Interview Data
Negative stressful life events.
Substance use.
Methylation, Genetic, and Gene Expression Data
Methylation.
Genetic.
Gene expression.
MRI Data Acquisition and Preprocessing
Data Analysis
Identification of differentially methylated regions.
Gene-environment interaction analysis.
Stress, methylation, and substance use.
Stress-methylation interaction analysis.
Gray matter volume and substance use.
Blood-brain methylation association.
Methylation-expression quantitative trait loci analyses.
Intra- and interchromosomal interactions between the SPDEF and trans-genes.
Results
Association of Differentially Methylated Regions With Frequency of Stressful Life Events
Variable | N | Mean | SD | Minimum | Maximum |
---|---|---|---|---|---|
Behavioral data | |||||
Frequency of negative stressful life events in the past year | 1,213 | 2.80 | 1.78 | 0 | 10 |
Emotional valence | 1,213 | –16.65 | 4.62 | –27 | 4 |
European School Survey Project on Alcohol and Other Drugs questionnaire | |||||
Lifetime smoking | 1,275 | 0.87 | 1.70 | 0 | 6 |
Lifetime alcohol use | 1,272 | 2.01 | 1.73 | 0 | 6 |
Lifetime binge drinking | 1,272 | 0.63 | 1.24 | 0 | 5 |
Genetic data | |||||
Methylation | |||||
Mean SPDEF | 1,287 | 0.45 | 0.26 | 0.10 | 0.83 |
SPDEF cg16527629 | 1,287 | 0.34 | 0.24 | 0.06 | 0.84 |
SPDEF cg01395541 | 1,287 | 0.57 | 0.28 | 0.13 | 0.92 |
Single-nucleotide polymorphism | |||||
Genotype | |||||
rs2233632 | 1,112 | 1.37 | 0.66 | ||
GG | 114 | ||||
GA | 468 | ||||
AA | 530 | ||||
rs2233631 | 1,112 | 1.38 | 0.66 | ||
GG | 114 | ||||
GA | 467 | ||||
AA | 531 | ||||
Gene expression | |||||
Illumina HumanHT–12 Version 4 Expression BeadChips | 660 | ||||
Neuroimaging data | |||||
T1 gray matter | 512 |
Allele-Specific Frequencies and Methylation Levels | |||||||||
---|---|---|---|---|---|---|---|---|---|
Gene (Gene Symbol) | Chr | p | Corrected p | Location | CpG Sites Located Within Differentially Methylated Region | SNPs | GG | GA | AA |
Sterile alpha motif/pointed domain containing ETS transcription factor (SPDEF) | 6 | 4.16×10–6 | 0.018 | Promoter | Cg01395541 | rs2233631 | 8.9%, N=114, M=0.82, SD=0.02 | 36.3%, N=467, M=0.83, SD=0.04 | 41.3%, N=531, M=0.27, SD=0.08 |
Cg16527629 | rs2233632 | 8.9%, N=114, M=0.77, SD=0.07 | 36.4%, N=468, M=0.48, SD=0.04 | 41.2%, N=530, M=0.10, SD=0.03 | |||||
Hook microtubule tethering protein 2 (HOOK2) | 19 | 4.86×10–6 | 0.021 | Covers exons | Cg04657146, Cg06417478, Cg11738485, Cg23899408 |
Genetic control of methylation levels.
Interaction between genotype, stress, and methylation.
Independent replication of interaction between stress and genotype with methylation.
Integrating SPDEF Methylation, Stress, and Substance Use
Associations between stress and substance use.
Associations between methylation and substance use.
Interaction of stress and methylation with substance use.
Interaction of stress and methylation with gray matter volume.
Blood-brain methylation association.
SPDEF Methylation and Gene Expression
Discussion
Footnote
Supplementary Material
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