Genome-wide association study of theta band event-related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence.

paper Primary Public

Authors: Zlojutro, Mark; Manz, Niklas; Rangaswamy, Madhavi; Xuei, Xiaoling; Flury-Wetherill, Leah; Koller, Daniel; Bierut, Laura J; Goate, Alison; Hesselbrock, Victor; Kuperman, Samuel; Nurnberger, John; Rice, John P; Schuckit, Marc A; Foroud, Tatiana; Edenberg, Howard J; Porjesz, Bernice; Almasy, Laura
Year: 2011
Journal: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
PMID: 21184583
DOI: 10.1002/ajmg.b.31136
PMCID: PMC3139811

Figure 1

Illustration of a standard P300 waveform and its time-frequency decompositionTop panel: visual oddball ERP waveforms from 48 normal, healthy control subjects. Bottom panel: time-frequency representation (TFR) plot for EEG responses to target stimuli. White box highlights the time-frequency region of interest (TFROI) and the inset head plot exhibits the frontal preponderance of the peak theta band activity.

LLM interpretation

This figure consists of a line plot (top) and a time-frequency representation (TFR) heatmap with an accompanying topographic head map (bottom). The top panel shows ERP waveforms at electrode Fz, where the "Target" (green) and "Novel" (blue) conditions exhibit a higher positive amplitude peak around 400ms compared to the "Non-Target" (red) condition. The bottom panel displays a TFR plot showing peak amplitude in the theta band (approximately 3-7 Hz) between 300-500ms, with the inset head map indicating this activity is concentrated frontally at Fz.

Figure 2

Schematic of two-stage association study of the theta ERO phenotype.

LLM interpretation

This figure is a flow diagram illustrating a two-stage association study for the theta ERO phenotype. Stage I (GWAS) involves a COGA case-control sample ($N=1,884$) undergoing genome-wide SNP genotyping and energy estimation, followed by association testing using the PLINK program. Stage II (Replication) utilizes a COGA family-based sample ($N=1,095$) for follow-up genotyping of 42 SNPs and family-based association analysis via the SOLAR package. The process concludes with a combined probability test using Fisher's Method to integrate results from both stages.

Figure 3

Quantile-quantile plot of genome-wide association resultsObserved P-values (y-axis) for theta ERO measurements are plotted for 951,071 SNPs against expected P-values (x-axis) under the null distribution for no association.

LLM interpretation

This is a quantile-quantile (Q-Q) plot comparing observed p-values against expected p-values for 951,071 SNPs associated with theta ERO measurements. Both axes are labeled as $-\log_{10}(P)$, with the x-axis representing expected values and the y-axis representing observed values. The data points closely follow the diagonal identity line for most of the distribution, with a visible upward deviation at the higher $-\log_{10}(P)$ values (above 4), indicating a subset of SNPs with stronger-than-expected associations.

Figure 4

Genome-wide association resultsP-values (−log10) for 951,071 SNPs are plotted in order of chromosome position.

LLM interpretation

This is a Manhattan plot showing genome-wide association results for 951,071 SNPs. The x-axis represents genomic position across chromosomes 1–22, and the y-axis displays the $-\log_{10}$ of the observed p-values. Several peaks of higher significance are visible, with the highest p-value peak occurring on chromosome 12.

#	Section	Preview
40	DISCUSSION	This paper presents the first genome-wide association study of an ERO phenotype – frontal theta…
41	DISCUSSION	observed, including rs1362178 (P = 0.0034) from GRM8 and rs17168817 (P = 0.033) from CHRM2. None of…
42	DISCUSSION	The results from the GWAS and follow-up analyses implicate several genes influencing theta EROs that…
43	DISCUSSION	locus with a complex, imprinted expression pattern for multiple transcripts, including the G-protein…
44	DISCUSSION	The other two significant SNPs to emerge from the two-stage association analysis are rs2294015, a…
45	DISCUSSION	The association signals observed at HTR7 are compelling, as they indicate important genetic effects…
46	DISCUSSION	eating disorders [Naughton et al., 2000; Hoyer et al., 2002; Nichols and Nichols, 2008]. The…
47	DISCUSSION	2004; Thomas and Hagan, 2004; Cifariello et al., 2008; Eriksson et al., 2008]. Pharmacologically,…
48	DISCUSSION	Hence, the association between HTR7 and alcohol dependence represents a novel insight into the…
49	DISCUSSION	Moreover, administration of 5-HT7 antagonists in adolescent rats has been shown to enhance…
50	DISCUSSION	In conclusion, this two-stage GWAS has identified four genes that may contribute to the expression…

Name	Type
5-HT7(a) local	variant
5-HT7 agonist local	drug
5-HT7 antagonist local	drug
5-HT7(b) local	variant
5-HT7(d) local	variant
5-HT7 receptor	drug
adolescent rats	cohort
affective disorders	phenotype
African American	cohort
African-Americans	cohort
age	phenotype
alcohol	phenotype
alcohol dependence	phenotype
Alcoholic proband	cohort
alcoholism	phenotype
alpha oscillations	phenotype
antidepressants	drug
antipsychotics	drug
ANXA13 local	gene
ARID5A local	gene
attention	phenotype
beta rhythm	phenotype
brain	anatomy
brain development	phenotype
brain oscillation features local	phenotype
brain oscillations	phenotype
Brain structure integrity local	phenotype
case-control data set local	cohort
case-control sample	cohort
cases	cohort
CDKN2B	gene
central	anatomy
cholinergic	drug
CHRM2	gene
Circadian rhythms	phenotype
clozapine	drug
cognition	phenotype
Collaborative Study on the Genetics of Alcoholism (COGA)	cohort
conscious awareness	phenotype
Control families	cohort
controls	cohort
Coriell Cell Repositories	cohort
dbGaP	cohort
decision-making	phenotype
Delta band ERO amplitude local	phenotype
delta rhythm	phenotype
depression	phenotype
Dopaminergic system	drug
eating disorder	phenotype
eating disorders	phenotype
EEG	phenotype
electrophysiological markers local	phenotype
Electrophysiological measures	phenotype
epilepsy	phenotype
episodic memory	phenotype
European-American individuals local	cohort
European ancestry	cohort
European population	cohort
event-related oscillations	phenotype
event-related oscillations (EROs)	phenotype
Event-related oscillatory responses local	phenotype
event-related potentials (ERPs) local	phenotype
exploratory behavior	phenotype
externalizing behavior	phenotype
externalizing disorders	phenotype
family-based replication data local	cohort
family-based sample	cohort
Family-based samples local	cohort
frontal cortex	anatomy
frontal inhibitory control	phenotype
Frontal midline channel (Fz electrode) local	anatomy
frontal theta ERO local	phenotype
frontal theta oscillations local	phenotype
GABA	phenotype
GABRA2	gene
gamma oscillations	phenotype
glutamate	drug
GNAS1 local	gene
GRM8	gene
GSα local	drug
GSα local	gene
GWAS	cohort
GWAS case-controls local	cohort
GWAS cases	cohort
GWAS data set local	cohort
haplotype G-T-G local	variant
Head injury	phenotype
Hepatic encephalopathy/cirrhosis of the liver local	phenotype
high-density affected family local	cohort
High-risk children of alcoholics local	cohort
high-risk subjects	cohort
hippocampus	anatomy
Htr2a	gene
Htr7	gene
HTR7 G allele local	variant
HTR7 haplotypes local	variant
illicit drug dependence	phenotype
impulsivity	phenotype
increased reactivity to novel environments local	phenotype
learning and memory	phenotype
limbic system	anatomy
memory	phenotype
midline frontal electrode (Fz) local	anatomy
migraine	phenotype
MTAP	gene
multiplex alcohol dependence pedigrees local	cohort
NESP55 local	gene
NESP55 knockout mice local	cohort
neurite length local	phenotype
neuroelectrical activity local	phenotype
neuroendocrine secretory protein 55 local	drug
Neurosurgical procedure local	phenotype
neurotransmitters	drug
Nor-adrenergic local	drug
NRN1 local	gene
NXPH1	gene
obsessive-compulsive disorder	phenotype
offspring of alcoholics	cohort
Other illicit substance abuse local	phenotype
P300 component	phenotype
P300 ERP local	phenotype
P300 ERP amplitude local	phenotype
P300 measures	phenotype
parietal cortex	anatomy
phs000125.v1.p1 local	cohort
promising SNPs local	variant
psychosis	phenotype
psychotropic medication	drug
recognition memory	phenotype
reward system	anatomy
risk-taking behavior	phenotype
risperidone	drug
rs11186309 local	variant
rs1362178 local	variant
rs13831 local	variant
rs17168817 local	variant
rs17512142 local	variant
rs1935351 local	variant
rs2294015 local	variant
rs2299498 local	variant
rs2784 local	variant
rs4907240 local	variant
rs7314987 local	variant
rs7916403	variant
schizophrenia	phenotype
Serotonergic system	drug
serotonin	drug
sex	phenotype
signal evaluation local	phenotype
signal transduction factors local	drug
sleep	phenotype
SNP	cohort
social phobia	phenotype
stimulus processing	phenotype
striatum	anatomy
substance abuse	phenotype
SUDS3 local	gene
synaptic plasticity	phenotype
TAOK3 local	gene
TFROI	anatomy
thalamocortical region local	anatomy
thalamocortical regions	anatomy
Theta band ERO amplitude local	phenotype
theta ERO	phenotype
theta ERO energy local	phenotype
Theta ERO phenotype local	phenotype
theta ERO reductions local	phenotype
theta EROs	phenotype
theta ERO sample subset local	cohort
theta oscillations	phenotype
unrelated individuals cohort local	cohort
visual oddball paradigm local	phenotype

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In this knowledge base

Title	Year	PMID
A KCNJ6 gene polymorphism modulates theta oscillations during reward processing.	2017	27993610
Endophenotype best practices.	2017	27473600
Genetic correlates of the development of theta event related oscillations in adolescents and young adults.	2017	27847216
Advances in Electrophysiological Research.	2015	26259089
Endophenotypes for Alcohol Use Disorder: An Update on the Field.	2015	26236574
Gender modulates the development of theta event related oscillations in adolescents and young adults.	2015	26102560
Gene expression changes in serotonin, GABA-A receptors, neuropeptides and ion channels in the dorsal raphe nucleus of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking.	2015	25542586
Reward processing deficits and impulsivity in high-risk offspring of alcoholics: A study of event-related potentials during a monetary gambling task.	2015	26388585
Ethanol treatment of lymphoblastoid cell lines from alcoholics and non-alcoholics causes many subtle changes in gene expression.	2014	25129674
Genetic psychophysiology: advances, problems, and future directions.	2014	24739435
Genome-wide association discoveries of alcohol dependence.	2014	25278008
Heritability and molecular-genetic basis of the P3 event-related brain potential: a genome-wide association study.	2014	25387705
Knowns and unknowns for psychophysiological endophenotypes: integration and response to commentaries.	2014	25387720
Common biological networks underlie genetic risk for alcoholism in African- and European-American populations.	2013	23607416
Stress-response pathways are altered in the hippocampus of chronic alcoholics.	2013	23981442
Convergence of genome-wide association and candidate gene studies for alcoholism.	2012	22978509
Event-Related Oscillations in Alcoholism Research: A Review.	2012	24273686
Family-based genome-wide association study of frontal θ oscillations identifies potassium channel gene KCNJ6.	2012	22554406
The genetics of alcohol dependence: advancing towards systems-based approaches.	2012	22854292
Theta event-related synchronization is a biomarker for a morbid effect of alcoholism on the brain that may partially resolve with extended abstinence.	2012	23170242

External

Title	Authors	Journal	Year	Link
Inhibitory and excitatory conditioned cues associated with alcohol differentially modulate the nucleus accumbens shell: involvement of 5-HT<sub>7</sub> receptors.	Hauser SR et al.	—	2025	→
The collaborative study on the genetics of alcoholism: Brain function.	Meyers JL et al.	—	2023	→
The collaborative study on the genetics of alcoholism: Genetics.	Johnson EC et al.	—	2023	→
International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function.	Barnes NM et al.	—	2021	→
Prefrontal cortex eQTLs/mQTLs enriched in genetic variants associated with alcohol use disorder and other diseases.	Lin H et al.	—	2020	→
Electrophysiology as a theoretical and methodological hub for the neural sciences.	Cavanagh JF	—	2019	→
Structure-activity relationships of serotonin 5-HT<sub>7</sub> receptors ligands: A review.	Thirumaran SL et al.	—	2019	→
5-HT<sub>1A</sub> parital agonism and 5-HT<sub>7</sub> antagonism restore episodic memory in subchronic phencyclidine-treated mice: role of brain glutamate, dopamine, acetylcholine and GABA.	Huang M et al.	—	2018	→
Serotonin functioning and adolescents' alcohol use: A genetically informed study examining mechanisms of risk.	Wang FL et al.	—	2018	→
A KCNJ6 gene polymorphism modulates theta oscillations during reward processing.	Kamarajan C et al.	—	2017	→
Alcohol and nicotine codependence-associated DNA methylation changes in promoter regions of addiction-related genes.	Xu H et al.	—	2017	→
Comorbidity of Alcohol Use Disorder and Chronic Pain: Genetic Influences on Brain Reward and Stress Systems.	Yeung EW et al.	—	2017	→
Endophenotype best practices.	Iacono WG et al.	—	2017	→
Genetic correlates of the development of theta event related oscillations in adolescents and young adults.	Chorlian DB et al.	—	2017	→
Genetic polymorphisms in the serotonin receptor 7 (HTR7) gene are associated with cortisol levels in African American young adults	Swanson G et al.	—	2017	—
What can time-frequency and phase coherence measures tell us about the genetic basis of P3 amplitude?	Malone SM et al.	—	2017	→
A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction.	Bell RL et al.	—	2016	→
Cellular Taxonomy of the Mouse Striatum as Revealed by Single-Cell RNA-Seq.	Gokce O et al.	—	2016	→
Evidence for genetic regulation of the human parieto-occipital 10-Hz rhythmic activity.	Salmela E et al.	—	2016	→
Genetic effects on source level evoked and induced oscillatory brain responses in a visual oddball task.	Antonakakis M et al.	—	2016	→
Advances in Electrophysiological Research.	Kamarajan C et al.	—	2015	→
Clinically relevant genetic biomarkers from the brain in alcoholism with representation on high resolution chromosome ideograms.	Manzardo AM et al.	—	2015	→
Endophenotypes for Alcohol Use Disorder: An Update on the Field.	Salvatore JE et al.	—	2015	→
Gender modulates the development of theta event related oscillations in adolescents and young adults.	Chorlian DB et al.	—	2015	→
Gene expression changes in serotonin, GABA-A receptors, neuropeptides and ion channels in the dorsal raphe nucleus of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking.	McClintick JN et al.	—	2015	→
Genome-wide association studies in Africans and African Americans: expanding the framework of the genomics of human traits and disease.	Peprah E et al.	—	2015	→
Inhibitory control in otherwise healthy overweight 10-year-old children.	Reyes S et al.	—	2015	→
Pharmacotherapy for alcohol dependence: A stratified approach.	Thompson A et al.	—	2015	→
Reward processing deficits and impulsivity in high-risk offspring of alcoholics: A study of event-related potentials during a monetary gambling task.	Kamarajan C et al.	—	2015	→
Serotonergic Systems in the Pathophysiology of Ethanol Dependence: Relevance to Clinical Alcoholism.	Marcinkiewcz CA	—	2015	→
Serotonin 7 Receptor Variants Are Not Associated with Response to Second-Generation Antipsychotics in Japanese Schizophrenia Patients.	Takekita Y et al.	—	2015	→
Shared additive genetic influences on DSM-IV criteria for alcohol dependence in subjects of European ancestry.	Palmer RH et al.	—	2015	→
Association between HTR7 genetic polymorphisms and alcohol dependence, using the alcohol use disorders identification test (AUDIT).	Kim JH et al.	—	2014	→
Ethanol treatment of lymphoblastoid cell lines from alcoholics and non-alcoholics causes many subtle changes in gene expression.	McClintick JN et al.	—	2014	→
Genetic psychophysiology: advances, problems, and future directions.	Anokhin AP	—	2014	→
Genetics of alcohol dependence: a review of clinical studies.	Samochowiec J et al.	—	2014	→
Genetics of alcoholism.	Iyer-Eimerbrink PA et al.	—	2014	→
Genome-wide association discoveries of alcohol dependence.	Zuo L et al.	—	2014	→
Heritability and molecular-genetic basis of the P3 event-related brain potential: a genome-wide association study.	Malone SM et al.	—	2014	→
Knowns and unknowns for psychophysiological endophenotypes: integration and response to commentaries.	Iacono WG et al.	—	2014	→
Pharmacogenomics in psychiatry: the relevance of receptor and transporter polymorphisms.	Reynolds GP et al.	—	2014	→
The 5-HT7 receptor as a potential target for treating drug and alcohol abuse.	Hauser SR et al.	—	2014	→
A family history of substance dependence obscures the group differences in brain function associated with HIV-1 and ART.	Bauer LO	—	2013	→
Alcoholism and liver disease in Mexico: genetic and environmental factors.	Roman S et al.	—	2013	→
Common biological networks underlie genetic risk for alcoholism in African- and European-American populations.	Kos MZ et al.	—	2013	→
Multi-cultural association of the serotonin transporter gene (SLC6A4) with substance use disorder.	Cao J et al.	—	2013	→
P300 amplitude reduction is associated with early-onset and late-onset pathological substance use in a prospectively studied cohort of 14-year-old adolescents.	Perlman G et al.	—	2013	→
Stress-response pathways are altered in the hippocampus of chronic alcoholics.	McClintick JN et al.	—	2013	→
Alcohol intake.	Corella D	—	2012	→
An unbiased evaluation of gene prioritization tools.	Börnigen D et al.	—	2012	→
Convergence of genome-wide association and candidate gene studies for alcoholism.	Olfson E et al.	—	2012	→
Event-Related Oscillations in Alcoholism Research: A Review.	Pandey AK et al.	—	2012	→
Family-based genome-wide association study of frontal θ oscillations identifies potassium channel gene KCNJ6.	Kang SJ et al.	—	2012	→
Genome-wide association study identifies 5q21 and 9p24.1 (KDM4C) loci associated with alcohol withdrawal symptoms.	Wang KS et al.	—	2012	→
The genetics of alcohol dependence: advancing towards systems-based approaches.	Palmer RH et al.	—	2012	→
Theta event-related synchronization is a biomarker for a morbid effect of alcoholism on the brain that may partially resolve with extended abstinence.	Gilmore CS et al.	—	2012	→
Confirmation of prior evidence of genetic susceptibility to alcoholism in a genome-wide association study of comorbid alcoholism and bipolar disorder.	Lydall GJ et al.	—	2011	→