Genetic overlap between ADHD symptoms and EEG theta power
Introduction
Attention deficit hyperactivity disorder (ADHD) is a relatively common childhood-onset neurodevelopmental disorder characterised by deficits in attention and/or hyperactivity and impulsivity (American Psychiatric Association, 2000). While family and twin studies demonstrate increased rates of ADHD in closely related family members, the findings from molecular genetic studies have yielded small effect sizes (Faraone et al., 2005). This might be explained by the highly complex and heterogeneous nature of ADHD, such that a number of different underlying cognitive and neural mechanisms and multiple genes of small effect and rare genes of large effect may result in the behavioural profile (Kuntsi, McLoughlin, & Asherson, 2006). It is now widely documented that continuously distributed traits underlie the categorical diagnosis of complex disorders, such as ADHD, that may provide more power to identify quantitative trait loci (Chen et al., 2008, Levy et al., 1997, Wood and Neale, 2010). There is increasing interest, therefore, in identifying quantitative markers of disorders that are associated with the normal variation of these traits. Accordingly, one approach to refine the ADHD phenotype is the identification of quantitative cognitive or neurobiological processes that increase risk for the disorder and mediate between genes and behaviour (Castellanos and Tannock, 2002, Doyle et al., 2005). In order to be viable, the main criteria state that the candidate trait must have good metric properties, be associated with the disorder, heritable, and share genetic influences with the disorder (Gottesman and Gould, 2003, Waldman, 2005, Walters and Owen, 2008).
Electroencephalographic (EEG) power represents a continuous measure with no floor or ceiling effects; lower frequency bands (4–13 Hz), in particular, show high temporal stability (Smit, Posthuma, Boomsma, & de Geus, 2005) and test–retest reliability (Williams et al., 2005). Accumulating evidence suggests that EEG is highly heritable and associated with specific genetic variants (McLoughlin et al., 2014, Tye et al., 2011). Specifically for EEG theta power, an early study of adolescent twin pairs demonstrated a heritability of 89% (van Beijsterveldt, Molenaar, De Geus, & Boomsma, 1996). More recently, heritability estimates of theta power have been estimated at a mean of 0.85 in young adults, with a range of 0.82–0.90 across scalp regions (Smit et al., 2005). In a multivariate analysis of EEG frequency bands, theta power heritability was highest in occipital regions (0.85) compared to frontal regions (0.64) (Zietsch et al., 2007).
While associations between ADHD and other EEG frequency bands are more variable, the most consistent EEG abnormality in ADHD is increased low-frequency activity; predominantly high levels of absolute and relative theta in frontal and central regions (Barry et al., 2003, El-Sayed et al., 2002, Mann et al., 1992, Monastra et al., 2001, Monastra et al., 1999, Quintana et al., 2007, Shi et al., 2012, Snyder and Hall, 2006, Snyder et al., 2008). Elevated theta persists into adolescence and adulthood (Bresnahan et al., 1999, Bresnahan and Barry, 2002, Koehler et al., 2009), and sensitivity and specificity rates support theta power as a potential diagnostic tool for ADHD (Quintana et al., 2007; Snyder & Hall, 2006; Snyder et al., 2008). Theta power measured at rest is associated with drowsy states and reduced arousal compared to higher frequency bands, thus increased theta in ADHD has been interpreted as a maturational delay marked by underarousal (Barry et al., 2003, Lazzaro et al., 1999, Sergeant, 2000). Collectively, the findings suggest that theta-indexed cortical underarousal is a robust marker of ADHD.
High heritability combined with consistent associations with ADHD provides rationale for investigation of theta power as a biological marker of genetic risk for ADHD. Studies to date, however, are limited. A preliminary study of affected sibling pairs with ADHD indicated sibling correlations for absolute theta power were highest in frontal regions during resting (0.57) that increased for a cognitive activation condition (0.69; Loo & Smalley, 2008), supported by, albeit lower, correlations in a larger study of multiplex families with ADHD (resting: 0.25; cognitive activation: 0.30; Loo et al., 2010). Family studies that use mean comparison analyses are not able to partition familial variance into genetic and environmental contributions and the amount of familial overlap is not quantified. Using structural equation modelling in twin samples, however, it is possible to explore whether this association is due to shared genetic influences using the different levels of genetic relatedness between monozygotic (MZ) and dizygotic (DZ) twin pairs (Neale & Cardon, 1992).
The present study aimed to validate the use of theta power as a marker of genetic risk ADHD by demonstrating heritability and genetic overlap with the disorder. Theta power was measured at rest in a twin sample selected for consistently high or low ADHD symptoms. Based on previous findings, we expected (a) theta power to be moderately to highly heritable, (b) increased theta to be found in individuals with higher ADHD symptom scores, and (c) moderate genetic correlations between these theta and ADHD symptoms, to support theta power as a candidate marker of genetic risk.
Section snippets
Sample
The sample consisted of 67 male twin pairs aged between 12 and 15 years in groups of 22 pairs concordant for high levels of ADHD symptoms (MZ: 11; DZ: 11), 8 pairs discordant for ADHD symptoms (MZ: 2; DZ: 6) and 37 control pairs concordant for low levels of ADHD symptoms (MZ: 21; DZ: 16). Individuals with high ADHD symptoms were slightly younger (mean age = 14.00 years) than those with low ADHD symptoms (mean age = 14.51 years; p > .05). Twin pairs were selected based on an analysis of symptom
Results
Theta power was highest in frontal regions and was significantly increased in frontal locations in the ADHD group compared to the control group (Table 1). There were trends towards increased theta power in central and parietal regions also. Theta power in frontal regions was subsequently used in twin modelling analyses.
The MZ cross-twin within-trait correlation for theta power (r = 0.79; 95% CI, 0.60 to 0.89) was greater than the DZ cross-twin within-trait correlation for theta power (r = 0.13; 95%
Discussion
In this study, we investigated the association between ADHD and EEG theta power during a resting condition as one of the most consistent neural markers of the disorder, and its potential as a marker of genetic risk in a selected sample of twins concordant and discordant for ADHD symptoms. Genetic analyses showed that theta power at rest was highly heritable. In addition, adolescents with consistently high ADHD symptom scores displayed elevated theta power at rest. Further, genetic factors were
Acknowledgments
The authors gratefully acknowledge the participating families and all staff involved in this study, in particular, Chloe Booth, Sarah Lewis, Stuart Newman, the TEDS research team and the Director of TEDS, Robert Plomin. The PI(GM) was supported by a fellowship from the National Institute for Health Research.
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