Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: A review of human brain oscillations as effective endophenotypes

Abstract

Brain oscillations provide a rich source of potentially useful endophenotypes (intermediate phenotypes) for psychiatric genetics, as they represent important correlates of human information processing and are associated with fundamental processes from perception to cognition. These oscillations are highly heritable, are modulated by genes controlling neurotransmitters in the brain, and provide links to associative and integrative brain functions. These endophenotypes represent traits that are less complex and more proximal to gene function than either diagnostic labels or traditional cognitive measures, providing a powerful strategy in searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, providing a more direct connection with underlying biological vulnerability. Our group has utilized heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We have discussed our findings of significant linkage and association between brain oscillations and genes in GABAergic, cholinergic and glutamatergic systems (GABRA2, CHRM2, and GRM8). We have also shown that some oscillatory indices from both resting and active cognitive states have revealed a common subset of genetic foci that are shared with the diagnosis of alcoholism and related disorders. Implications of our findings have been discussed in the context of physiological and pharmacological studies on receptor function. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of brain function and the genetic diathesis underlying complex psychiatric disorders.

Genetic and Neurophysiological Correlates of the Age of Onset of Alcohol Use Disorders in Adolescents and Young Adults

“…Representation of this response in terms of brain rhythms or event-related oscillations (EROs) has proved fruitful (Rangaswamy and Porjesz, 2008; Jones et al, 2006a; Gilmore et al, 2010). The ERO amplitudes used in this study were obtained from responses to rare target stimuli that elicited a P3 component in a visual oddball experiment at three midline leads (Fz, Cz, Pz).…”

“…That genetic factors have an age-specific influence on the onset of alcohol dependence is suggested by the findings that there are strong genetic effects contributing to risk for alcohol dependence particularly connected with early onset of drinking activity (Rangaswamy and Porjesz, 2008; Sartor et al, 2009; Agrawal et al, 2009; Xuei et al, 2010; Kendler et al, 2011; Lee et al, 2012). Correspondingly, the rate of adult alcohol dependence is significantly greater among those who start drinking at a relatively early age (14 years or younger) than among those who start drinking after the age of 19 (Grant and Dawson, 1997) (see also Hingson et al (2006a, b); Hussong et al (2008); Chen et al (2011)).…”

Systems Biology and Addiction

“…Molecular patterns of rhythmic activities impact on all molecular systems (networks) including neurotransmitters. Therefore, any transmitter system in the brain may oscillate and resonate in a rhythmic way and amplitudes and frequencies of these oscillations may infl uence one another in a signifi cant way through environmental stimuli and also by " psychoactive substances " , like drugs and psychiatric medications [1,32,62,71,88] . In this regard, the brain is a multicomponent electrochemical " oscillator " with actions that are partially agonistic or partially out of phase and even antagonistic (cf.…”

Understanding alcohol use disorders with neuroelectrophysiology

“…As seen in this review, neuroelectrophysiological measures (e.g., P3, theta ERO, EEG beta) that differentiate between alcoholics and controls, and between HR offspring from densely affected alcoholic families and LR controls, serve as effective endophenotypes (intermediate phenotypes that correlate with diagnosis). These endophenotypes are under genetic control and are highly heritable, and have been successfully used in the search for genes associated with risk for AUDs and related disorders (Porjesz and Rangaswamy, 2007; Rangaswamy and Porjesz, 2008a, b). As the genomic technologies have evolved from linkage scans with microsatellites to candidate gene studies and genomewide association studies (GWAS) these studies have highlighted targets that have proved to be relevant to understanding the pathophysiology of AUDs.…”

“…In the COGA study, significant linkage for theta (6–7 Hz) interhemispheric coherence at parieto-occipital regions led to significant association with several single nucleotide polymorphisms (SNPs) in GABRA2 . Another significant linkage peak for theta (6–7 Hz) centroparietal coherence was significantly associated with SNPs in CHRM2 , a cholinergic muscarinic receptor gene (Porjesz and Rangaswamy, 2007; Rangaswamy and Porjesz, 2008b). …”