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
0	INTRODUCTION	Brain oscillations are salient features of active neural networks, with specific frequency rhythms…
1	INTRODUCTION	The electroencephalogram (EEG) records brain electrical activity using non-invasive scalp electrodes…
2	INTRODUCTION	Recent studies involving time-frequency domain analysis have determined that ERPs may not be unitary…
3	INTRODUCTION	Generally, EROs have been analyzed using traditional EEG frequency band limits: delta (1-3 Hz);…
4	INTRODUCTION	These oscillatory responses have served as useful endophenotypes for measuring and deconstructing…
5	INTRODUCTION	responses have identified several chromosome regions and genetic variants that underpin these…
6	INTRODUCTION	In the present paper, we report the results of the first genome-wide association study (GWAS) of an…
7	METHODS — Sample Recruitment and Assessment	The samples included in this study were recruited and tested as part of the multi-site Collaborative…
8	METHODS — Sample Recruitment and Assessment	Recruitment and assessment procedures have been outlined previously [Begleiter et al., 1995; Reich…
9	METHODS — Sample Recruitment and Assessment	All recruited individuals and participating family members were administered a validated…
10	METHODS — GWAS Case-Control Sample	All alcohol-dependent cases and controls in the GWAS sample (N = 1,884) are genetically unrelated.…
11	METHODS — GWAS Case-Control Sample	among two subgroups characterized as being of either European (74.3%; N = 1,399) or African ancestry…
12	METHODS — Family-Based Replication Sample	For the second stage, forty-two promising SNPs from the GWAS were tested for association with theta…
13	METHODS — Electrophysiological Data Collection	All seven collaborating sites used identical experimental procedures and EEG acquisition hardware…
14	METHODS — ERO Energy Estimation	Estimates of localized energy of non-stationary event-related potential time series were obtained…
15	METHODS — ERO Energy Estimation	Visual oddball event-related electrophysiological data for the target conditions were analyzed. Mean…
16	METHODS — ERO Energy Estimation	For the GWAS sample, a total of 1,064 theta ERO measurements were recorded (with ±4 SD outliers…
17	METHODS — GWAS Genotyping and Quality Control	Genotyping was performed by the Center for Inherited Disease Research (CIDR) at John Hopkins…
18	METHODS — GWAS Genotyping and Quality Control	Additional quality control measures were applied to the dbGaP data for both the samples and the…
19	METHODS — Replication Genotyping	After reviewing the results from the primary genome-wide association analysis, top-ranking SNPs were…

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

Citation	PMID	DOI	Status
Abecasis, GR et al., European Journal of Human Genetics, 2000, Pedigree tests of transmission disequilibrium	10909856	10.1038/sj.ejhg.5200494	Cited
Agrawal, A et al., Drug and Alcohol Dependence, 2008, Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample	17942244	10.1016/j.drugalcdep.2007.08.015	Primary
Almasy, L et al., American Journal of Human Genetics, 1998, Multipoint quantitative-trait linkage analysis in general pedigrees	9545414	10.1086/301844	Cited
Almasy, L et al., American Journal of Medical Genetics, 1999, Heritability of event-related brain potentials in families with a history of alcoholism	10402506	—	Primary
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 1987	—	—	—
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 1994	—	—	—
Barrett, JC et al., Bioinformatics, 2005, Haploview: analysis and visualization of LD and haplotype maps	15297300	10.1093/bioinformatics/bth457	Cited
Basar, E et al., International Journal of Psychophysiology, 2000, Brain oscillations in perception and memory	10677641	10.1016/s0167-8760(99)00047-1	Cited
Basar, E et al., International Journal of Psychophysiology, Gamma, alpha, delta, and theta oscillations govern cognitive processes	11163901	10.1016/s0167-8760(00)00145-8	Cited
Basar, E et al., International Journal of Psychophysiology, The selectively distributed theta system: functions	11163897	10.1016/s0167-8760(00)00141-0	Cited
Basar, E et al., Neuroscience Letters, 1999, Are cognitive processes manifested in event-related gamma, alpha, theta and delta oscillations in the EEG?	10025584	10.1016/s0304-3940(98)00934-3	Cited
Bastepe, M, Curr Genomics, 2007, The GNAS Locus: Quintessential Complex Gene Encoding Gsalpha, XLalphas, and other Imprinted Transcripts	19412439	10.2174/138920207783406488	Cited
Begleiter, H et al., Electroencephalography and Clinical Neurophysiology, 1995, Event-related brain potentials differentiate priming and recognition to familiar and unfamiliar faces	7530638	10.1016/0013-4694(94)00240-l	Cited
Begleiter, H et al., International Journal of Psychophysiology, 2006, Genetics of human brain oscillations	16540194	10.1016/j.ijpsycho.2005.12.013	Primary
Boerwinkle, E et al., Annals of Human Genetics, 1986, The use of measured genotype information in the analysis of quantitative phenotypes in man. I. Models and analytical methods	3435047	10.1111/j.1469-1809.1986.tb01037.x	Cited
Bucholz, KK et al., Journal of Studies on Alcohol, 1994, A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA	8189735	10.15288/jsa.1994.55.149	Primary
Buhot, MC et al., Annals of Medicine, 2000, Role of serotonin in memory impairment	10821328	10.3109/07853890008998828	Cited
Buzsaki, G, Rhythms of the Brain, 2006	—	—	—
Chen, AC et al., American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2009, Association of single nucleotide polymorphisms in a glutamate receptor gene (GRM8) with theta power of event-related oscillations and alcohol dependence	18618593	10.1002/ajmg.b.30818	Primary
Cifariello, A et al., Behavioural Brain Research, 2008, 5-HT(7) receptors in the modulation of cognitive processes	18243350	10.1016/j.bbr.2007.12.012	Cited
de Bakker, PIW et al., Nature Genetics, 2005, Efficiency and power in genetic association studies	16244653	10.1038/ng1669	Cited
Devlin, B et al., Biometrics, 1999, Genomic control for association studies	11315092	10.1111/j.0006-341x.1999.00997.x	Cited
Dick, DM et al., Addiction, 2007, Alcohol dependence with comorbid drug dependence: genetic and phenotypic associations suggest a more severe form of the disorder with stronger genetic contribution to risk	17567401	10.1111/j.1360-0443.2007.01871.x	Primary
Doppelmayr, M et al., Neuroscience Letters, 1998, Theta synchronization in the human EEG and episodic retrieval	9857961	10.1016/s0304-3940(98)00805-2	Cited
Edenberg, HJ et al., Addiction Biology, 2006, The genetics of alcoholism: identifying specific genes through family studies	16961766	10.1111/j.1369-1600.2006.00035.x	Primary
Edenberg, HJ et al., Alcoholism: Clinical and Experimental Research, 2010, Genome-wide association study of alcohol dependence implicates a region on chromosome 11	20201924	10.1111/j.1530-0277.2010.01156.x	Primary
Edenberg, HJ et al., American Journal of Human Genetics, 2004, Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations	15024690	10.1086/383283	Primary
Eriksson, TM et al., European Journal of Pharmacology, 2008, 5-HT7 receptor stimulation by 8-OH-DPAT counteracts the impairing effect of 5-HT(1A) receptor stimulation on contextual learning in mice	18789922	10.1016/j.ejphar.2008.08.026	Cited
Feighner, JP et al., Archives of General Psychiatry, 1972, Diagnostic criteria for use in psychiatric research	5009428	10.1001/archpsyc.1972.01750190059011	Cited
Fisher, RA, Statistical Methods for Research Workers, 1925	—	—	—
Ford, JM et al., Electroencephalography and Clinical Neurophysiology, 1994, The relationship between P300 amplitude and regional gray matter volumes depends upon the attentional system engaged	7511503	10.1016/0013-4694(94)90093-0	Cited
Ford, JM, Psychophysiology, 1999, Schizophrenia: the broken P300 and beyond	10554581	—	Cited
Foroud, T et al., Alcoholism, Clinical and Experimental Research, 2000, Alcoholism susceptibility loci: confirmation studies in a replicate sample and further mapping	10923994	—	Primary
Fries, P, Trends Cogn Sci, 2005, A mechanism for cognitive dynamics: neuronal communication through neuronal coherence	16150631	10.1016/j.tics.2005.08.011	Cited
Frodl-Bauch, T et al., Neuropsychobiology, 1999, Neurochemical substrates and neuroanatomical generators of the event-related P300	10474063	10.1159/000026603	Cited
Gabriel, SB et al., Science, 2002, The structure of haplotype blocks in the human genome	12029063	10.1126/science.1069424	Cited
Ge, D et al., WGAViewer User’s Guide: Whole Genome Association Annotation Software Package, 2007	—	—	—
Gelernter, J et al., Biological Psychiatry, 2009, Dense genomewide linkage scan for alcohol dependence in African Americans: significant linkage on chromosome 10	18930185	10.1016/j.biopsych.2008.08.036	Cited
Gevins, A et al., Human Factors, 1998, Monitoring working memory load during computer-based tasks with EEG pattern recognition methods	9579105	10.1518/001872098779480578	Cited
Gruber, WR et al., Cerebral Cortex, 2005, Alpha phase synchronization predicts P1 and N1 latency and amplitude size	15749980	10.1093/cercor/bhh139	Cited
Gunderson, KL et al., Methods in Enzymology, 2006, Whole-genome genotyping	16938560	10.1016/S0076-6879(06)10017-8	Cited
Harada, J et al., Journal of Neurochemistry, 2004, Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells	14756825	10.1046/j.1471-4159.2003.02219.x	Cited
Havill, LM et al., BMC Genet, 2005, The quantitative trait linkage disequilibrium test: a more powerful alternative to the quantitative transmission disequilibrium test for use in the absence of population stratification	16451707	10.1186/1471-2156-6-S1-S91	Cited
Hedlund, PB et al., Proceedings of the National Academy of Sciences of the United States of America, 2003, No hypothermic response to serotonin in 5-HT7 receptor knockout mice	12529502	10.1073/pnas.0337340100	Cited
Hedlund, PB et al., Trends in Pharmacological Sciences, 2004, Functional, molecular and pharmacological advances in 5-HT7 receptor research	15559250	10.1016/j.tips.2004.07.002	Cited
Heidmann, DE et al., Journal of Neurochemistry, 1997, Four 5-hydroxytryptamine7 (5-HT7) receptor isoforms in human and rat produced by alternative splicing: species differences due to altered intron-exon organization	9084407	10.1046/j.1471-4159.1997.68041372.x	Cited
Heidmann, DE et al., Neuropharmacology, 1998, Function and distribution of three rat 5-hydroxytryptamine7 (5-HT7) receptor isoforms produced by alternative splicing	9886685	10.1016/s0028-3908(98)00070-7	Cited
Hesselbrock, M et al., Addiction, 1999, A validity study of the SSAGA--a comparison with the SCAN	10615721	10.1046/j.1360-0443.1999.94913618.x	Primary
Hoyer, D et al., Pharmacology, Biochemistry and Behavior, 2002, Molecular, pharmacological and functional diversity of 5-HT receptors	11888546	10.1016/s0091-3057(01)00746-8	Cited
Iacono, WG et al., International Journal of Psychophysiology, 2003, Substance use disorders, externalizing psychopathology, and P300 event-related potential amplitude	12763572	10.1016/s0167-8760(03)00052-7	Cited
Ikeda, M et al., Neuropsychopharmacology, 2006, Positive association of the serotonin 5-HT7 receptor gene with schizophrenia in a Japanese population	16192982	10.1038/sj.npp.1300901	Cited
Jasper, JR et al., British Journal of Pharmacology, 1997, Cloning, expression and pharmacology of a truncated splice variant of the human 5-HT7 receptor (h5-HT7b)	9298538	10.1038/sj.bjp.0701336	Cited
Jones, KA et al., Behavior Genetics, A cholinergic receptor gene (CHRM2) affects event-related oscillations	16823639	10.1007/s10519-006-9075-6	Primary
Jones, KA et al., Clinical Neurophysiology, S-transform time-frequency analysis of P300 reveals deficits in individuals diagnosed with alcoholism	16926113	10.1016/j.clinph.2006.02.028	Primary
Jones, KA et al., International Journal of Psychophysiology, 2004, Linkage and linkage disequilibrium of evoked EEG oscillations with CHRM2 receptor gene polymorphisms: implications for human brain dynamics and cognition	15210286	10.1016/j.ijpsycho.2004.02.004	Primary
Kanzawa, T et al., Oncogene, 2006, Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway	16491125	10.1038/sj.onc.1209414	Cited
Karakas, S et al., Clinical Neurophysiology, A new strategy involving multiple cognitive paradigms demonstrates that ERP components are determined by the superposition of oscillatory responses	11018485	10.1016/s1388-2457(00)00418-1	Cited
Karakas, S et al., Neuroscience Letters, The genesis of human event-related responses explained through the theory of oscillatory neural assemblies	10788704	10.1016/s0304-3940(00)01022-3	Cited
Katsanis, J et al., Psychophysiology, 1997, P300 event-related potential heritability in monozygotic and dizygotic twins	9009808	10.1111/j.1469-8986.1997.tb02415.x	Cited
Klimesch, W et al., Brain Research Cognitive Brain Research, 2001, Theta synchronization during episodic retrieval: neural correlates of conscious awareness	11489606	10.1016/s0926-6410(01)00024-6	Cited
Klimesch, W et al., Brain Research Cognitive Brain Research, Event-related desynchronization in the alpha band and the processing of semantic information	9450602	10.1016/s0926-6410(97)00018-9	Cited
Klimesch, W et al., Electroencephalography and Clinical Neurophysiology, 1994, Episodic and semantic memory: an analysis in the EEG theta and alpha band	7529682	10.1016/0013-4694(94)90164-3	Cited
Klimesch, W et al., Neuroscience Letters, 1997, Brain oscillations and human memory: EEG correlates in the upper alpha and theta band	9464642	10.1016/s0304-3940(97)00771-4	Cited
Lachaux, JP et al., Journal of Neuroscience Methods, 2003, A simple measure of correlation across time, frequency and space between continuous brain signals	12606066	10.1016/s0165-0270(02)00358-8	Cited
Lange, K et al., Genetic Epidemiology, 1988, Programs for Pedigree Analysis: MENDEL, FISHER, and dGENE	3061869	10.1002/gepi.1370050611	Cited
Leo, D et al., Genes, Brain and Behavior, 2009, Methylphenidate to adolescent rats drives enduring changes of accumbal Htr7 expression: implications for impulsive behavior and neuronal morphology	19243449	10.1111/j.1601-183X.2009.00486.x	Cited
Llinas, R et al., Proceedings of the National Academy of Sciences of the United States of America, 1993, Coherent 40-Hz oscillation characterizes dream state in humans	8446632	10.1073/pnas.90.5.2078	Cited
Makeig, S et al., Science, 2002, Dynamic brain sources of visual evoked responses	11809976	10.1126/science.1066168	Cited
Manolio, TA et al., Nature, 2009, Finding the missing heritability of complex diseases	19812666	10.1038/nature08494	Cited
McCarley, RW et al., Archives of General Psychiatry, 1993, Auditory P300 abnormalities and left posterior superior temporal gyrus volume reduction in schizophrenia	8439239	10.1001/archpsyc.1993.01820150036003	Cited
Naughton, M et al., Hum Psychopharmacol, 2000, A review of the role of serotonin receptors in psychiatric disorders	12404302	10.1002/1099-1077(200008)15:6<397::AID-HUP212>3.0.CO;2-L	Cited
Nichols, DE et al., Chemical Reviews, 2008, Serotonin receptors	18476671	10.1021/cr078224o	Cited
Nurnberger, JI et al., Archives of General Psychiatry, 2004, A family study of alcohol dependence: coaggregation of multiple disorders in relatives of alcohol-dependent probands	15583116	10.1001/archpsyc.61.12.1246	Primary
O’Connell, JR et al., American Journal of Human Genetics, 1998, PedCheck: a program for identification of genotype incompatibilities in linkage analysis	9634505	10.1086/301904	Cited
O’Connor, S et al., Electroencephalography and Clinical Neurophysiology, 1994, Heritable features of the auditory oddball event-related potential: peaks, latencies, morphology and topography	7511509	10.1016/0168-5597(94)90052-3	Cited
Padmanabhapillai, A et al., International Journal of Psychophysiology, Evoked gamma band response in male adolescent subjects at high risk for alcoholism during a visual oddball task	16887227	10.1016/j.ijpsycho.2006.05.012	Primary
Padmanabhapillai, A et al., International Journal of Psychophysiology, Suppression of early evoked gamma band response in male alcoholics during a visual oddball task	16019097	10.1016/j.ijpsycho.2005.03.026	Primary
Patsialou, A et al., Nucleic Acids Res, 2005, DNA-binding properties of ARID family proteins	15640446	10.1093/nar/gki145	Cited
Plagge, A et al., Journal of Endocrinology, 2008, Physiological functions of the imprinted Gnas locus and its protein variants Galpha(s) and XLalpha(s) in human and mouse	18252944	10.1677/JOE-07-0544	Cited
Plagge, A et al., Molecular and Cellular Biology, 2005, Imprinted Nesp55 influences behavioral reactivity to novel environments	15798190	10.1128/MCB.25.8.3019-3026.2005	Cited
Polich, J et al., International Journal of Psychophysiology, 2000, P300 as a clinical assay: rationale, evaluation, and findings	11027791	10.1016/s0167-8760(00)00127-6	Cited
Polich, J, Clinical Neurophysiology, 2007, Updating P300: an integrative theory of P3a and P3b	17573239	10.1016/j.clinph.2007.04.019	Cited
Porjesz, B et al., Alcoholism, Clinical and Experimental Research, 1998, Amplitude of visual P3 event-related potential as a phenotypic marker for a predisposition to alcoholism: preliminary results from the COGA Project. Collaborative Study on the Genetics of Alcoholism	9756048	—	Primary
Porjesz, B et al., Clinical Neurophysiology, 2005, The utility of neurophysiological markers in the study of alcoholism	15826840	10.1016/j.clinph.2004.12.016	Primary
Porjesz, B et al., Journal of Clinical Neurophysiology, 1998, Genetic basis of event-related potentials and their relationship to alcoholism and alcohol use	9502512	10.1097/00004691-199801000-00006	Primary
Price, AL et al., Nature Genetics, 2006, Principal components analysis corrects for stratification in genome-wide association studies	16862161	10.1038/ng1847	Cited
Psychiatric GWAS Consortium Coordinating Committee, American Journal of Psychiatry, 2009, Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders	19339359	10.1176/appi.ajp.2008.08091354	Cited
Purcell, S et al., American Journal of Human Genetics, PLINK: a tool set for whole-genome association and population-based linkage analyses	17701901	10.1086/519795	Cited
Purcell, S et al., Bioinformatics, WHAP: haplotype-based association analysis	17118959	10.1093/bioinformatics/btl580	Cited
Rangaswamy, M et al., Brain Research, 2008, Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: a review of human brain oscillations as effective endophenotypes	18634760	10.1016/j.brainres.2008.06.053	Primary
Rangaswamy, M et al., International Journal of Psychophysiology, 2007, Delta and theta oscillations as risk markers in adolescent offspring of alcoholics	17129626	10.1016/j.ijpsycho.2006.10.00	Primary
Reich, T et al., American Journal of Medical Genetics, 1998, Genome-wide search for genes affecting the risk for alcohol dependence	9603606	—	Primary
Roberts, AJ et al., European Journal of Neuroscience, 2004, Mice lacking 5-HT receptors show specific impairments in contextual learning	15078565	10.1111/j.1460-9568.2004.03288.x	Cited
Roth, BL et al., Journal of Pharmacology and Experimental Therapeutics, 1994, Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors	7908055	—	Cited
Rueda, D et al., Journal of Biological Chemistry, 2002, The endocannabinoid anandamide inhibits neuronal progenitor cell differentiation through attenuation of the Rap1/B-Raf/ERK pathway	12237305	10.1074/jbc.M206590200	Cited
Schurmann, M et al., International Journal of Psychophysiology, 2001, Delta responses and cognitive processing: single-trial evaluations of human visual P300	11163900	10.1016/s0167-8760(00)00144-6	Cited
Schurmann, M et al., Neuroreport, 1997, Gamma responses in the EEG: elementary signals with multiple functional correlates	9080442	10.1097/00001756-199701200-00030	Cited
Sprouse, J et al., Neuropharmacology, 2004, 8-OH-DPAT as a 5-HT7 agonist: phase shifts of the circadian biological clock through increases in cAMP production	14654097	10.1016/j.neuropharm.2003.08.007	Cited
Stockwell, RG et al., IEEE Trans Signal Process, 1996, Localization of the complex spectrum: the S-transform	—	—	—
Stockwell, RG, Pseudo-Differential Operators: Partial Differential Equations and Time-Frequency Analysis, 2007, Why use the ST	—	—	—
Taylor, J et al., Genome Research, 2006, ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements	17053093	10.1101/gr.4537706	Cited
Thomas, DR et al., British Journal of Pharmacology, 2003, SB-656104-A, a novel selective 5-HT7 receptor antagonist, modulates REM sleep in rats	12812993	10.1038/sj.bjp.0705290	Cited
Thomas, DR et al., Curr Drug Targets CNS Neurol Disord, 2004, 5-HT7 receptors	14965246	10.2174/1568007043482633	Cited
Tomberg, C et al., Neuroscience Letters, 1998, Human perceptual processing: inhibition of transient prefrontal-parietal 40 Hz binding at P300 onset documented in non-averaged cognitive brain potentials	9832198	10.1016/s0304-3940(98)00740-x	Cited
Tsuang, MT et al., American Journal of Medical Genetics, 2000, The frustrating search for schizophrenia genes	10813798	10.1002/(sici)1096-8628(200021)97:1<1::aid-ajmg1>3.0.co;2-p	Cited
Turnay, J et al., Biochemical Journal, 2005, Structure-function relationship in annexin A13, the founder member of the vertebrate family of annexins	15813707	10.1042/BJ20041918	Cited
van Beijsterveldt, CE et al., American Journal of Human Genetics, 1996, Heritability of human brain functioning as assessed by electroencephalography	8644716	—	Cited
van Beijsterveldt, CE et al., Human Genetics, 1994, Genetics of the human electroencephalogram (EEG) and event-related brain potentials (ERPs): a review	7927323	10.1007/BF00201587	Cited
Verleger, R, Behavioral and Brain Sciences, 1988, Event-related potentials and cognition: a critique of the context updating hypothesis and an alternative interpretation of P3	—	—	—
Wang, JC et al., Human Molecular Genetics, 2004, Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome	15229186	10.1093/hmg/ddh194	Primary
Weiss, U et al., Neuroendocrinology, 2000, Neuroendocrine secretory protein 55 (NESP55): alternative splicing onto transcripts of the GNAS gene and posttranslational processing of a maternally expressed protein	10729789	10.1159/000054535	Cited
Williams, JT et al., American Journal of Human Genetics, 1999, Joint multipoint linkage analysis of multivariate qualitative and quantitative traits. II. Alcoholism and event-related potentials	10486334	10.1086/302571	Primary
Wilsker, D et al., Cell Growth and Differentiation, 2002, ARID proteins: a diverse family of DNA binding proteins implicated in the control of cell growth, differentiation, and development	11959810	—	Cited
World Health Organization, The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research, 1993	—	—	—
Zhang, W et al., Biochemical and Biophysical Research Communications, 2000, Cloning of DPK, a novel dendritic cell-derived protein kinase activating the ERK1/ERK2 and JNK/SAPK pathways	10924369	10.1006/bbrc.2000.3244	Cited

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	→