QTLs Identified for P3 Amplitude in a Non-Clinical Sample: Importance of Neurodevelopmental and Neurotransmitter Genes

Wright, Margaret J.; Luciano, Michelle; Hansell, Narelle K.; Montgomery, Grant W.; Geffen, Gina; Martin, Nicholas G.

doi:10.1016/j.biopsych.2007.09.002

Cited by 9 publications

(8 citation statements)

References 111 publications

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“…Although such detailed knowledge for P3AR is lacking as yet, it is beginning to be uncovered for other brain‐derived endophenotypes, providing proof, in principle, that endophenotypes may provide substantive etiological insights (Erk et al., 2010; Hodgkinson et al., 2010; Roeske et al., 2011). In addition, many studies have reported associations between P300 amplitude and specific genes or chromosomal loci (Begleiter et al., 1998; Chen et al., 2010; Comings, Dietz, Johnson, & MacMurray, 1999; Hill et al., 1998; Johnson et al., 1997; Porjesz & Rangaswamy, 2007; Williams et al., 1999; Wright et al., 2008). However, in the absence of replication of these reports of molecular genetic correlates of P300, it would be premature to conclude that a solid lead on the molecular genetic basis of P300 has been established.…”

Section: What Is An Endophenotype?mentioning

confidence: 99%

Developmental Endophenotypes: Indexing Genetic Risk for Substance Abuse With the P300 Brain Event-Related Potential

Iacono

Malone

2011

Child Development Perspectives

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Although substance use disorders are heritable, their complexity has made identifying genes underlying their development challenging. Endophenotypes, biologically informed quantitative measures that index genetic risk for a disorder, are being recognized for their potential to assist the search for disorder relevant genes. After outlining criteria for an endophenotype that includes developmental considerations, we review how the brain P300 response serves as an index of genetic risk for substance abuse and related externalizing disorders. The P300 response is highly heritable and associated broadly with characteristics of externalizing disorder, including childhood disruptive disorders, antisociality, and precocious expression of deviant behavior. This association appears to be mediated by shared genetic influences. Prospective studies confirm that reduced P300 amplitude present in youth prior to significant exposure to addictive substances is associated with the subsequent development of substance use disorders. Despite pronounced change in mean level over the course of development, P300 amplitude shows strong rank order stability with repeated assessment through young adulthood. In addition, P300 developmental trajectories based on multiple assessments show very high heritability and may be especially informative as measures of genetic risk. Collectively, these findings provide strong support that P300 amplitude and its change through development reflect genetic vulnerability to substance abuse and related externalizing psychopathology.Most scientists trying to unravel the genetic basis of substance use disorders (SUDs) have been both surprised and frustrated by how difficult it has been to identify the etiologically relevant genes. Although there are likely many reasons for the slow rate of progress, one explanation reflects concern over the adequacy of the Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association. Although the DSM provides clinically useful descriptions, its characterization of disorder is not biologically based. DSM categories may therefore not be optimal for facilitating gene identification. This concern has led to the hope that alternative phenotypes can be identified that more efficiently capture genetic risk associated with disorder development. Endophenotypes, so called because they reflect some endogenous quantitative attribute best measured using a laboratory procedure, constitute one such alternative phenotype.For substance use disorders, the best candidate endophenotype derives from the amplitude of the P300 wave of the visual event-related potential. This positive voltage brain signal has an onset latency of about 300 milliseconds in simple speeded reaction time tasks and is typically elicited by stimuli that stand out when embedded in a series of like stimuli because they are rare and require a response such as a button press. Figure 1 illustrates stimuli and brain responses from the "rotated heads" paradigm (introduced by Begleiter et al., 1984) use...

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Section: What Is An Endophenotype?mentioning

confidence: 99%

Developmental Endophenotypes: Indexing Genetic Risk for Substance Abuse With the P300 Brain Event-Related Potential

Iacono

Malone

2011

Child Development Perspectives

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“…A meta-analysis based on twin studies with measures of P300 amplitude shows a heritability of 60% (30), further suggesting the likelihood that P300 amplitude is transmitted across generations. How the transmission of reduced P300 amplitude across generations becomes translated into increased risk for AD is currently unknown, though several investigations have addressed possible candidate genes (31,32). …”

Section: P300 Disinhibition and Risk For Admentioning

confidence: 99%

Childhood Risk Factors for Young Adult Substance Dependence Outcome in Offspring from Multiplex Alcohol Dependence Families: A Prospective Study

Hill¹,

Steinhauer²,

Locke-Wellman³

et al. 2009

Biological Psychiatry

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Background Age of onset to begin drinking is a known risk factor for alcohol dependence. Factors have been identified that contribute to age of onset to begin regular drinking. These include reduced P300, increased postural sway, and personality variation. A longitudinal study spanning childhood to young adulthood provided the opportunity to determine if these same factors would predict the presence and onset of substance use disorders (SUD). Methods Multiplex families were identified through two or more alcohol-dependent brothers. Offspring from these multiplex or control families (n = 133) were followed annually during childhood. Using childhood predictors previously identified as risk factors for age of onset to begin drinking, SUD outcome by young adulthood was modeled. Results Familial risk status was a significant predictor of young adult SUD outcome as a main effect and as an interaction with P300 amplitude recorded before the age of 13. In adolescence (age 15), increased postural sway and familial risk predicted the SUD outcome by age 22. Analysis comparing the presence of one or both risk factors showed that those above the median for sway and below the median for P300 amplitude had substantially increased odds of developing SUD (odds ratio = 8.08 [confidence interval = 1.52– 42.83]). Conclusions Our findings indicate that among the factors predicting age of onset to begin regular drinking, P300 predicts SUD outcome across an 11-year span. The present findings provide the longest follow-up to date demonstrating that neurobiological factors in childhood are among the most salient predictors of young adult SUD outcome.

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“…The search for genetic markers associated with P3 amplitude has met limited success. Linkage studies have implicated regions of several chromosomes, principally 4, 6, 7, and 12 (Begleiter et al., ; Hill et al., ; Williams et al., ; Wright et al., ; H. Zhang, Zhong, & Ye, ). However, linkage analysis by itself can only highlight relatively large segments on a given chromosome.…”

mentioning

confidence: 99%

“…The search for genetic markers associated with P3 amplitude has met limited success. Linkage studies have implicated regions of several chromosomes, principally 4, 6, 7, and 12 (Begleiter et al, 1998;Hill et al, 2004;Williams et al, 1999;Wright et al, 2008;H. Zhang, Zhong, & Ye, 2005).…”

mentioning

confidence: 99%

Heritability and molecular‐genetic basis of the P3 event‐related brain potential: A genome‐wide association study

et al. 2014

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P3 amplitude is a candidate endophenotype for disinhibitory psychopathology, psychosis, and other disorders. The present study is a comprehensive analysis of the behavioral- and molecular-genetic basis of P3 amplitude and a P3 genetic factor score in a large community sample (N = 4,211) of adolescent twins and their parents, genotyped for 527,829 single nucleotide polymorphisms (SNPs). Biometric models indicated that as much as 65% of the variance in each measure was due to additive genes. All SNPs in aggregate accounted for approximately 40% to 50% of the heritable variance. However, analyses of individual SNPs did not yield any significant associations. Analyses of individual genes did not confirm previous associations between P3 amplitude and candidate genes but did yield a novel association with myelin expression factor 2 (MYEF2). Main effects of individual variants may be too small to be detected by GWAS without larger samples.

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QTLs Identified for P3 Amplitude in a Non-Clinical Sample: Importance of Neurodevelopmental and Neurotransmitter Genes

Cited by 9 publications

References 111 publications

Developmental Endophenotypes: Indexing Genetic Risk for Substance Abuse With the P300 Brain Event-Related Potential

Developmental Endophenotypes: Indexing Genetic Risk for Substance Abuse With the P300 Brain Event-Related Potential

Childhood Risk Factors for Young Adult Substance Dependence Outcome in Offspring from Multiplex Alcohol Dependence Families: A Prospective Study

Heritability and molecular‐genetic basis of the P3 event‐related brain potential: A genome‐wide association study

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