American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:1461– 1469 (2008)
Serotonin Transporter Gene and Adverse Life Events in Adult ADHD Daniel J. Mu ¨ ller,1,2 Laura Mandelli,3 Alessandro Serretti,3* Colin G. DeYoung,4 Vincenzo De Luca,2 Tricia Sicard,2 Subi Tharmalingam,2 Ju ¨ rgen Gallinat,1 Pierandrea Muglia,2 Diana De Ronchi,3 Umesh Jain,2 and James L. Kennedy2** 1
Department of Psychiatry, Charite´ University Medicine Berlin, Campus Mitte, Berlin, Germany Neurogenetics Section, Centre for Addiction and Mental Health (CAMH), University of Toronto, Ontario, Canada 3 Institute of Psychiatry, University of Bologna, Bologna, Italy 4 Department of Psychology, Yale University, New Haven, Connecticut 2
Childhood attention deficit hyperactivity disorder (ADHD) symptomatology persists in a substantial proportion of cases into adult life. ADHD is highly heritable but the etiology of ADHD is complex and heterogeneous, involving both genetic and non-genetic factors. In the present article we analyzed the influence of both genetics and adverse life events on severity of ADHD symptoms in 110 adult ADHD patients. Subjects were genotyped for the norepinephrine transporter (NET), the catechol-O-methyltransferase (COMT), the serotonin transporter promoter polymorphism (SERTPR) and the more rare A/G variant within SERTPR. Three main outcomes were obtained: (1) adverse events showed a small but positive correlation with current ADHD severity; (2) NET, COMT and the A/G variant within SERTPR were not associated with ADHD severity; (3) taking into account stressors, the long (L) SERTPR variant showed a mild effect on ADHD, being associated with an increased severity, particularly as regard affective dysregulations; on the other hand, in subjects exposed to early stressors, it showed a protective effect, as compared to the short (S) variant. In conclusion, our data support the role of environmental factors in adult ADHD symptomatology. SERTPR may be involved in some features of the illness and act as a moderator of environmental influences in ADHD. ß 2008 Wiley-Liss, Inc. KEY WORDS:
adult ADHD; gene environment interaction; serotonin transporter gene; life events
Grant sponsor: Canadian Institutes of Health Research (CIHR). *Correspondence to: Dr. Alessandro Serretti, M.D., Institute of Psychiatry, University of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy. E-mail:
[email protected] **Correspondence to: James L. Kennedy, M.D., Neurogenetics Section Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto 250 College Street R30, Toronto, ON, Canada M5T 1R8. E-mail:
[email protected] Received 7 November 2006; Accepted 28 November 2007 DOI 10.1002/ajmg.b.30706 Published online 23 January 2008 in Wiley InterScience (www.interscience.wiley.com)
ß 2008 Wiley-Liss, Inc.
Please cite this article as follows: Mu ¨ ller DJ, Mandelli L, Serretti A, DeYoung CG, De Luca V, Sicard T, Tharmalingam S, Gallinat J, Muglia P, De Ronchi D, Jain U, Kennedy JL. 2008. Serotonin Transporter Gene and Adverse Life Events in Adult ADHD. Am J Med Genet Part B 147B:1461–1469.
INTRODUCTION Attention deficit hyperactivity disorder (ADHD) is the most common cognitive, emotional, and behavioral disorder in children [American Psychiatric Association, 1994; Faraone et al., 2000]. The disorder is characterized by inattention (difficulty to sustain attention, forgetfulness, and distractibility), hyperactivity (fidgeting, excessive talking, restlessness), and impulsivity (difficulty waiting one’s turn, frequent interruption of others). ADHD affects approximately 8–12% of children and thus is more prevalent than schizophrenia, obsessive-compulsive disorder, and panic disorder [Biederman, 2005]. Symptoms of the disorder are known to persist into adult life in a substantial proportion of cases [Faraone et al., 2006], predisposing to significant levels of academic, occupational, and social impairment [Harpin, 2005]. Further, adult ADHD is associated with a high risk for comorbid psychiatric disorders [Biederman et al., 1991, 2006], including alcohol and drug abuse [Kalbag and Levin, 2005], antisocial behavior [Thapar et al., 2006], anxiety, depression [Weinberg and Emslie, 1991], and bipolar disorder [Shekim et al., 1990]. There is strong evidence that ADHD is highly heritable and has a neurobiological underpinning [Faraone and Biederman, 1999]. Brain alterations observed in ADHD include significantly smaller volumes in the dorsolateral prefrontal cortex, caudate, pallidum, corpus callosum, and cerebellum [Seidman et al., 2005]. The most critical neurotransmitters in ADHD are dopamine and norepinephrine, both of which exert modulatory influences on working memory and attentional functions in the prefrontal cortex [Arnsten, 1997]. Catecholamine dysfunctions have been supposed to induce dysregulation both of the inhibitory influences of frontal cortex activity, which is predominantly noradrenergic, and of lower striatal structures, which are predominantly dopaminergic [Zametkin and Rapoport, 1987; Zametkin and Liotta, 1998]. Recent studies suggest that also the serotoninergic pathway may be involved in the response to psychostimulants, which are the first-line treatment drugs for ADHD [Solanto, 1998; Gainetdinov et al., 1999]. Molecular candidate genes studies have implicated mainly dopamine pathway genes, such as the dopamine transporter (DAT), D4 and D5 postsynaptic receptors (DRD2 and DRD5; for
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a recent review see Waldman and Gizer [2006]). The noradrenergic and serotonergic neurotransmitter pathways have been investigated to a lesser extent. Recently, several studies have examined association and linkage between ADHD and catechol-O-methyltransferase (COMT), an enzyme responsible for the degradation of dopamine and norepinephrine. Although some evidence for association was obtained in males with the inattentive ADHD sub-type [Qian et al., 2003], negative results are more common [Bobb et al., 2005; Cheuk and Wong, 2006; Waldman and Gizer, 2006]. The gene that codes for the norepinephrine transporter (NET) has recently received attention as a candidate gene for ADHD. NET is a solute carrier protein responsible for the reuptake of norepinephrine from the synaptic cleft back to the presynaptic neuron; it is highly expressed in the frontal lobes, and thus represents an important mechanism for the regulation of noradrenergic activity in the prefrontal cortex [Stahl, 2003]. To our knowledge, three studies investigated genetic variants for NET in childhood ADHD [Barr et al., 2002; McEvoy et al., 2002; Bobb et al., 2005] and only one in adulthood [De Luca et al., 2004a]; only one study reported a positive association [Bobb et al., 2005]. Results of the NET gene in this sample were published previously by a family based approach including subjects’ parents [De Luca et al., 2004a]. Regarding the serotonin pathway, more studies have recently been conducted (see Waldman and Gizer [2006]). In particular, the serotonin transporter (SERT) has been examined as a potential causal factor in ADHD. SERT is a solute carrier protein responsible for the reuptake of serotonin from the synaptic cleft back to the presynaptic neuron. The 44-bp insertion/deletion in the promoter region of SERT (SERTPR) has been reported to be positively associated with ADHD [Kent et al., 2002; Zoroglu et al., 2002; Beitchman et al., 2003; Curran et al., 2005], particularly with the inattentive sub-type [Manor et al., 2001; Seeger et al., 2001]. However, negative reports do also exist [Langley et al., 2003; Xu et al., 2005]. Recently, an A/G single nucleotide polymorphism has been described within the promoter polymorphism [Nakamura et al., 2000]. In functional terms, the long SERTPR variant containing the G allele seemed to behave like the short variant [Hu et al., 2006]. This polymorphism, however, was not found to be associated to ADHD [Wigg et al., 2006]. Literature documents that psychosocial adversities are also strong risk factors for ADHD [Biederman et al., 1995]. In fact, higher adversity index scores have been related to the presence of ADHD and to comorbid symptoms of depression, anxiety, conduct disorder, and learning disability [Biederman et al., 1995, 1996, 2002]. Individual risk factors that made the strongest contribution to ADHD risk were low socioeconomic status, parental psychopathology, and family conflict [Scahill et al., 1999; Biederman et al., 2002]. However, the relationship between adverse life events and genetic factors modulating the severity of adult ADHD has not been analyzed yet. In the present study we investigated potential gene–environment interactions in adult ADHD by taking into account both adverse life events and genetic variants of the SERTPR, the NET, and the COMT genes. METHODS Sample and Evaluations The sample was composed by 110 Caucasian adults (71 males and 39 females), aged 32.7 9.5 (range: 17–56). More details regarding sociodemographic data and diagnostic assessment can be found elsewhere [Muglia et al., 2000, 2002]. Briefly, a diagnosis of ADHD was determined by DSM-IV [American Psychiatric Association, 1994] criteria including additional criteria such as a score >46 on the Wender Utah Rating Scale
(WURS) [Ward et al., 1993], >55 on the Brown Attention Deficit Disorder Scale (BADDS) [Brown, 1996], and >60 on the Conner’s Adult ADHD Rating Scale (CAARS) [Conners et al., 1997]. Self-report instruments, such as the WURS, the BADDS, and CAARS have all been psychometrically evaluated and found valid and reliable as diagnostic aids for adult ADHD [Ward et al., 1993; Brown, 1996; Conners, 1999]. Sub-scales of the BADDS were included in our analyses; the BADDS scores were used to assess cross-sectional adult ADHD severity. The Structured Interview for DSM-IV (SCID-I) [First et al., 1995] was employed to assess for other psychiatric symptoms and comorbid diagnoses. If a comorbid diagnosis emerged as predominating and potentially accounting for ADHD symptomatology, the subject was excluded from the analyses. The rating scales were administered by trained interviewers blind with respect to the genotypes of the probands. The study was approved by the Research Ethics Board of the Adult ADHD Clinic, Centre for Addiction and Mental Health, Toronto, and written informed consent to participate in the study was obtained from all participants. Occurrence of adverse life events was assessed by an interview with 61 items evaluating stressors in childhood and, to a lower extent, across the lifetime. Stressors investigated were selected from those reported in literature as associated with psychiatric disorders (e.g., regarding ADHD: [Blanz et al., 1991; Allen et al., 1998; Cuffe et al., 2001; Counts et al., 2005]). Adult stressors were evaluated according to the most common instruments [Paykel et al., 1971; Brown and Harris, 1978] (see Table AI for a detailed description of the items). The number of life events was summed to produce an ordinal scale. This sum was subsequently categorized according to the lower-upper quartiles of its distribution in the whole sample. Quartiles were respectively 6 and 13, thus each subject was described as follows: experiencing few adverse life events (if 6 adverse life events, n ¼ 34), intermediate (if between 7 and 13 adverse life events, n ¼ 52), or many (if more than 13 adverse life events, n ¼ 24). Because stressful life-events experienced in childhood may have a particularly strong impact on the etiology of ADHD and its persistence into adulthood, we also analyzed childhood and adulthood life events separately. Total number of life events in childhood (all except the two last dimensions of ‘‘deaths in adulthood’’ and ‘‘other adverse life events in adult life’’) was categorized according to the lower-upper quartiles of this specific distribution (few: 3 n ¼ 28; intermediate: between 4 and 9 n ¼ 51; many: more than 9 n ¼ 31). The same procedure was applied when calculating scores for life events in adult-life (‘‘deaths in adulthood’’ and ‘‘other adverse life events in adult life’’): the lower and upper quartiles in this case were 2 and 5 (few: 2 n ¼ 50; intermediate: between 3 and 5 n ¼ 30; many: more than 5 n ¼ 30). Genetic Analysis Genomic DNA was extracted from white blood cells using a high salt extraction method [Lahiri and Nurnberger, 1991]. The genotyping was performed by the laboratory staff and was carried out blind to the psychiatric ratings. NET, COMT, SERTPR and the rare A/G variant within SERTPR were genotyped as previously reported [Stober et al., 1996; Bilder et al., 2002; Ishii et al., 2007]. Statistical Analysis Student t-test, analysis of variance (ANOVA) and correlation analysis were used when analyzing continuous dependent variables, Spearman’s r was used for life events, being an ordinal variable. Multivariate analysis of covariance (MANCOVA) was employed to control for sex and age. Multiple
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TABLE AI. Scale to Assess Stressful Life Events in Childhood and Adult Life Birth complications
Problems during mother’s pregnancy? Delivered by forceps? Neonatal complications/psychomotor retardation Problems with gross motor growth? Problems with speech? Late toileting? Problems sleeping as infant? Colicky baby? Difficult as a baby? Physical distress/medical condition between years 1 and 5 Head injury? Abnormal seizures? Prolonged ear infections? Tubes in ears? Other surgery? Hospitalizations (not for mental problems)? Respiratory problems? Allergies? Abuse Physical abuse? Sexual abuse? Verbal abuse? Alcoholic or abusing parent? Separation Parents separated before the age of 6? Parents separated between age 7 and 12? Parents separated between age 13 and 18? Deaths in childhood Death of one parent before the age of 6? Death of one parent between the age of 7 and 12? Death of one parent between the age of 13 and 18? Death of a sibling? Death of a close relative? Death of a close friend? Death of a close pet? Accident in childhood Accident with injury to self? Accident resulting in injury to others? Parental distress Remarriage of one/both parents? Birth or adoption of sibling? Parent and sibling conflict? Family financial stress? Parent unemployed? Parent hospitalized? Parent with mental illness? Frequent moving/school change More than 5 different schools? More than 5 moves? Violent familiar environment Physical fighting with parent? Observed parents physically fighting? Saw violence? Living in dangerous neighbourhood? Deaths in adulthood Death of your child? Death of a spouse? Death of a parent? Death of a significant relative? Death of a close friend? Death of a pet? Other negative life events in adulthood Separation or divorce? Custody battle? Significant injury to your child? Motor vehicle accident? Major catastrophe (e.g., flood, tornado)? Stressful work? Hospitalization? Significant embarrassing event? Major calamity? Significant breakup?
regression analysis was employed to control for sex and age in correlation analysis, as well as to analyze the effect of genotypes, adverse life-events and their interaction on BADDS scores, defined as the dependent variable. Genetic variations were included in the model as two dummy variables (i.e.,
presence/absence of each genotype) in order to circumvent a-priori hypothesis of linear codominance [Kai-Uwe Ku¨hn et al., 1999; Serretti et al., 1999; Lerer et al., 2001]. We considered results significant with a conservative alpha level of 0.01. With these parameters, we had sufficient power
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(0.80) to detect only large effect sizes (d ¼ 0.72–0.84) corresponding to a difference of 12.6 points on total BADDS scores between groups of subjects exposed to few/intermediate versus many adverse life events, and corresponding to a difference of 14.76 points between subjects grouped according to SERTPR genotype [Cohen, 1988]. RESULTS Demographic Correlates of Adult ADHD Sex and current age did not affect ADHD severity and dimensions. According to the WURS, in childhood only, males reported slightly higher inattention scores (t ¼ 2.1; d.f. ¼ 99; P ¼ 0.038) and more conduct disorder symptoms compared to females (t ¼ 2.7; d.f. ¼ 101; P ¼ 0.009). Conduct disorder scores in adulthood were correlated with young age (R ¼ 0.42; P < 0.0001). Genetics of ADHD All polymorphisms here considered were in Hardy– Weinberg equilibrium (Table I). Patients, grouped according genotypes, were not significantly different in gender and age (data not shown, all P values higher than 0.01, available on request). A MANCOVA analysis, controlling for sex and diagnosis, indicated that none of the gene variants predicted any of the BADDS scores (Table II). Even collapsing LA/LG and LA/S genotypes (n ¼ 48) and LG/S and S/S genotypes (n ¼ 27), according to Neumeister et al. [2006], no significant genetic effect was observed on ADHD severity. Nevertheless, though non-significantly, in our sample SERTPR*S/S subjects obtained medially more than 10 points lower BADDS scores than L/L individuals. Adverse Life Events and Adult ADHD In the present sample we observed a high rate of physical distress before the age of 6 (at least one problem in 70% of subjects). The rate of separation of parents was only 26% but at least one stressful familial event was reported in the 84% of cases; verbal, physical or sexual abuse was reported in the 55% of cases, accidents in the 49% of cases. The rate of deaths experienced was high in childhood (44%), and a little higher in adulthood (65%). In adulthood, at least one stressful event occurred in 86% of subjects. As regards to the number of lifeevents, 34% of subjects reported many adverse events and respectively 31% and 35% few or intermediate. Females reported more parental distress (t ¼ 2.7; d.f. ¼ 108; P ¼ 0.007), more deaths of relatives in childhood (t ¼ 2.8;
d.f. ¼ 108; P ¼ 0.005) and they also showed a trend to be exposed to overall more adverse life events (t ¼ 2.5; d.f. ¼ 108; P ¼ 0.013). Controlling for age and sex, life events showed a nonsignificant trend to affect overall ADHD severity (P ¼ 0.032; Table III). Number of adverse life events also showed a trend of association with ‘‘working memory& accessing recall’’ (P ¼ 0.036). Analyzing separately childhood and adulthood adverse life events, no any significant effect was observed on total BADDS scores, as well as on other sub-scales. Only birth complications showed a trend of positive correlation with severity of ‘‘Sustaining energy & effort’’ dimensions (P ¼ 0.026). Interaction Between Genetics and Childhood Adverse Life Events Given some impact of stressful events on current ADHD severity, we tested whether an interaction between genetics and life events could be detected. We performed a multiple regression analysis, including genetic variants as dummy variables (i.e., presence/absence of each genotype) in order to circumvent a-priori hypothesis of linear codominance [Kai-Uwe Ku¨hn et al., 1999; Serretti et al., 1999; Lerer et al., 2001], life events and the combination of each genotype with stressful events. Multiple regression models were not significant considering life stressors and each gene, neither for total BADDS scores (SERTPR: P ¼ 0.11; SERTPR*A/G: P ¼ 0.14; COMT: P ¼ 0.13; NET: P ¼ 0.09), nor for other sub-scales (all P-values >0.01). However, when entering in the model childhood life stressor only, some trend of association could be observed analyzing SERTPR, though the global regression model was not significant (P ¼ 0.10). We in fact observed some association between the presence of the L variant and higher total BADDS scores, between occurrence of stressors and higher total BADDS scores, and a protective effect of the L variant in the presence of early stressors (Table IV). The model was nearly significant when considering the dimension of ‘‘Managing affective interference’’ (P ¼ 0.014), with significant associations in the same direction of those previously observed on total BADDS scores (Table V). Considering childhood stressors only, SERTPR*A/G variants showed a less strong and nonsignificant association with the dimension of ‘‘Managing affective interference’’ (P ¼ 0.036), in the direction of more severe symptoms in LA allele carriers, but not with total BADDS scores or other sub-facets. Finally, COMT and NET genotypes were not associated with ADHD severity even when including number of childhood stressors. Adult stressors,
TABLE I. SERTPR, COMT, and NET Genotypes in 110 ADHD Patients (HWE: Hardy–Weinberg Equilibrium) Genotypes
Traditional SERTPR
N (%) N (%) L/L L/S 30 (30.3%) 46 (46.5%) A/G variant within SERTPR N (%) N (%) N (%) LA/LG LG/LG LA/LA 22 (22.2%) 9 (9.1%) 0 (0%) COMT Val/Val Val/Met 26 (26.3%) 52 (52.5%) NET 1/1 1/2 55 (51.9%) 44 (41.5%)
HWE P-values N (%) S/S 23 (23.2%)
LA/S 42 (42.4%)
N (%) LG/S 4 (4.1%)
N (%) S/S 22 (22.2%) Met/Met 21 (21.2%) 2/2 7 (6.6%)
P ¼ 0.33 HWE P-values P ¼ 0.48 HWE P-values P ¼ 0.60 HWE P-values P ¼ 0.65
21.12 4.09 20.52 4.37 19.43 5.32 F ¼ 0.56; d.f. ¼ 2; P ¼ 0.57
21.44 3.64 21.07 4.93 22.29 3.73 F ¼ 0.33; d.f. ¼ 2; P ¼ 0.71
20.8 3.8 21.3 4.2 22.5 3.8 F ¼ 0.54; d.f. ¼ 2; P ¼ 0.58
20.0 4.2 F ¼ 0.98; d.f. ¼ 4; P ¼ 0.42
19.1 4.3 F ¼ 2.59; d.f. ¼ 4; P ¼ 0.22
19.2 4.5 21.3 4.3 21.1 3.5 F ¼ 1.39; d.f. ¼ 2; P ¼ 0.25
22.5 3.6 21.6 4.2 21.1 4.7
22.4 3.5 21.1 4.6 20.0 4.4 F ¼ 2.09; d.f. ¼ 2; P ¼ 0.13
21.6 3.6 22.0 4.2 20.8 4.4
21.7 3.6 20.6 4.6 19.2 4.3 F ¼ 2.58; d.f. ¼ 2; P ¼ 0.08
Mean SD
Mean SD
19.88 5.12 18.93 5.10 16.86 7.73 F ¼ 1.09; d.f. ¼ 2; P ¼ 0.34
18.8 5.5 18.8 5.4 19.9 5.0 F ¼ 0.27; d.f. ¼ 2; P ¼ 0.76
18.8 5.5 F ¼ 0.27; d.f. ¼ 4; P ¼ 0.90
19.6 3.6 20.4 5.0 18.7 5.6
20.0 4.0 18.6 5.9 18.6 5.4 F ¼ 1.08; d.f. ¼ 2; P ¼ 0.34
Mean SD
Sustaining energy & effort
13.81 4.30 12.38 4.86 14.00 4.58 F ¼ 1.61; d.f. ¼ 2; P ¼ 0.20
13.3 4.7 12.7 4.4 15.1 4.6 F ¼ 2.03; d.f. ¼ 2; P ¼ 0.14
11.9 5.0 F ¼ 0.66; d.f. ¼ 4; P ¼ 0.62
13.6 4.1 13.6 3.9 13.7 5.0
13.6 4.1 13.7 4.9 12.0 5.0 F ¼ 0.83; d.f. ¼ 2; P ¼ 0.44
Mean SD
Managing affective interference
12.94 3.97 12.88 3.69 11.14 6.15 F ¼ 0.37; d.f. ¼ 2; P ¼ 0.69
11.2 4.8 13.6 3.5 12.7 4.3 F ¼ 2.15; d.f. ¼ 2; P ¼ 0.12
10.7 4.4 F ¼ 1.15; d.f. ¼ 4; P ¼ 0.34
13.4 4.8 14.0 2.3 12.8 3.5
13.6 4.3 12.8 3.5 11.0 4.5 F ¼ 1.68; d.f. ¼ 2; P ¼ 0.19
Mean SD
Working memory & accessing recall
89.19 17.05 85.79 18.59 83.71 24.49 F ¼ 0.71; d.f. ¼ 2; P ¼ 0.49
83.4 18.1 87.7 18.3 91.4 17.3 F ¼ 0.52; d.f. ¼ 2; P ¼ 0.59
80.6 18.8 F ¼ 0.96; d.f. ¼ 4; P ¼ 0.42
90.7 15.7 91.6 13.5 87.1 19.5
91.3 14.6 86.8 19.7 80.9 18.4 F ¼ 2.09; d.f. ¼ 2; P ¼ 0.13
Mean SD
Total BADDS scores
In bold trends of association (see text for details).
Number of adverse life events (few, intermediate, many) Childhood adverse life events (few, intermediate, many) Adulthood adverse life events (few, intermediate, many) Birth complications Childhood complications or medical conditions Physical distress/medical conditions before the age of 6 Childhood abuse Parents separated before the age of 18 Assisted deaths in childhood Accidents Parental distress Moving/school changes Violent familiar environment Deaths in adulthood Other negative life events in adulthood
0.16 0.15 0.08 0.22 0.08 0.09 0.00 0.02 0.08 0.03 0.10 0.04 0.16 0.07 0.05
Organizing & activating 0.19 0.15 0.19 0.08 0.08 0.06 0.06 0.10 0.00 0.05 0.14 0.02 0.13 0.05 0.15
Sustaining attention & concentration
0.15 0.11 0.10 0.21 0.11 0.04 0.01 0.01 0.01 0.16 0.05 0.04 0.13 0.06 0.11
Sustaining energy & effort
0.20 0.18 0.08 0.09 0.06 0.07 0.13 0.12 0.01 0.06 0.10 0.11 0.16 0.04 0.16
Managing affective interference
0.22 0.14 0.25 0.05 0.04 0.03 0.08 0.07 0.09 0.13 0.08 0.13 0.13 0.22 0.22
Working memory & accessing recall
0.23 0.18 0.17 0.17 0.08 0.05 0.07 0.06 0.04 0.11 0.11 0.07 0.17 0.11 0.17
Total BADDS scores
TABLE III. Correlations Between Stressful Life Events and ADHD Brown Dimensions for 105 ADHD Patients, Controlling for Age and Sex with Multiple Regression Analysis
Age and sex were controlled by the MANCOVA analysis.
NET G/G (n ¼ 52) G/A (n ¼ 42) A/A (n ¼ 7)
COMT Val/Val (n ¼ 23) Val/Met (n ¼ 50) Met/Met (n ¼ 21)
A/G within SERTPR LA/LA (n ¼ 20) LA/LG (n ¼ 8) LA/S (n ¼ 40) LG/S (n ¼ 4) S/S (n ¼ 23)
SERTPR L/L (n ¼ 28) L/S (n ¼ 44) S/S (n ¼ 23)
Sustaining attention & concentration
Organizing & activating
TABLE II. Brown Scales Scores in ADHD Patients, According to Genotypes
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TABLE IV. The Effect of Number of Childhood Stressors and SERTPR on Total BADDS Scores (Multiple Regression Analysis) Total BADDS scores No. of childhood adverse life events Presence of the S allele Presence of the L allele No. of life events presence of the S allele No. of life events presence of the L allele
b
P
1.63 0.34 0.68 0.68 1.19
0.022 n.s. 0.024 n.s. 0.037
combined with genetic variations, did not show any significant association with ADHD severity. In summary, the SERTPR*L variant showed an effect on ADHD symptoms, as regards in particular the dimension of Managing affective interference. Nevertheless, this finding emerged only after controlling for early adverse events. In our sample, both the number of stressors and the L allele increased BADDS scores; on the other hand, L allele carriers, exposed to many stressors, were somewhat more protected than those carrying the S allele. It has to be noticed that SERTPR genotypes were not associated with life-events per se, neither in childhood nor in adulthood, thus the effect of life stressors was independent from that of genotypes. The other genes were not associated with stressors per se as well. DISCUSSION ADHD is a complex disorder, where both genetic and environmental influences make a substantial contribution to the risk for the disorder [Faraone et al., 2000]. ADHD is well recognized in child psychiatry, whereas the impact of persistence of ADHD symptoms on adult psychopathology has yet to be fully appreciated [Asherson, 2005]. ADHD in adulthood appears to represent a more severe and more persistent form of the disorder, with a poorer outcome [Biederman et al., 2006]. The genetic component was suggested to be more pronounced in adult ADHD [Faraone et al., 2000], however, only few studies investigated etiological factors in adult ADHD [Johann et al., 2003; De Luca et al., 2004a,b; Lynn et al., 2005]. Moreover, structured works on genetic and environmental interactions in ADHD are substantially lacking. To our knowledge, this is the first report that focused on both genetic and environmental risk factors in adult ADHD. Three main results were obtained. First, in adults we found adverse life events showing a positive, though small, correlation with severity of ADHD symptomatology. In particular, life events worsened memory functioning; birth complications worsened the abilities to persist in activities. Animal studies have documented that stress in early life alters norepinephrine, serotonin, and dopamine neurotransmitter systems in ways that can persist into adulthood and can influence behaviors (e.g., [Kraemer et al., 1989; Bremne and Vermetten, 2001; Bennett et al., 2002]). Recently, animal-model studies reported that stress might also induce anatomical alterations
TABLE V. The Effect of Number of Childhood Stressors and SERTPR on the BADDS Sub-Facet of Managing Affective Interference (Multiple Regression Analysis) Managing affective interference No. of childhood adverse life events Presence of the S allele Presence of the L allele No. of life events presence of the S allele No. of life events presence of the L allele
b
P
2.17 0.58 0.97 0.83 1.65
0.002 n.s. 0.001 n.s. 0.003
in the prefrontal cortex and functional deficits in attentional control [Liston et al., 2006]. Second, consistently with previous articles, we found no evidence for an involvement of COMT [Cheuk and Wong, 2006; Waldman and Gizer, 2006] and NET polymorphisms [Barr et al., 2002; McEvoy et al., 2002] in ADHD. Regarding NET, the reader should however note that all studies, including the present one, selected markers only at the 30 end of the NET gene, thus other regions of the gene should be tested before excluding its involvement in ADHD. A similar observation can be made for COMT where only one polymorphism (val158met) has been studied thus far in relation to ADHD. Third, we observed a small effect of SERTPR on ADHD severity, but only when controlling for stressors occurring early in life. Previous findings on SERTPR reported an overrepresentation of the L allele in ADHD patients [Manor et al., 2001; Seeger et al., 2001; Kent et al., 2002; Zoroglu et al., 2002; Beitchman et al., 2003; Curran et al., 2005]. In our sample, we found a trend toward a more severe symptomatology in subjects carrying the L allele, particularly as regard the dimension of ‘‘organizing and activating,’’ compared to subjects carrying the S variant. On the other hand, the L variant showed a protective effect in subjects exposed to many stressors in childhood, which are risk factors for ADHD. This finding is intriguing, as it suggests that the opposite S variant, though not directly involved in ADHD, may lead to more severe symptoms in subjects exposed to adversities early in life. This effect of the S allele has been already demonstrated in depression and in anxiety disorders. The original study of Caspi et al. [2003] reported in fact an increased risk of developing psychopathological symptoms in S allele carriers, as compared to L/L subjects, if exposed to stressors. SERTPR was originally reported to be associated with anxiety-traits [Lesch et al., 1996], and, recently, there is increasing evidence that SERTPR is involved in the regulation of emotional adjustment of individuals [Hariri et al., 2003; Hariri and Holmes, 2006]. Overall, this genetic variant seems to mediate abnormal-psychopathological response to stressful life events. In line with this evidence, we found the L allele to be protective in patients exposed to many adverse life events, though at the same time, it was a risk factor for severe ADHD, however in line with previous association studies (see above). Nevertheless, a number of limitations characterize the present investigation. First of all, our sample was relatively small and we were able to detect only large effect sizes. Thus smaller effects may have been lost. Another major limitation is the nature of assessment of adverse life events. The retrospective assessment of adverse life events can allow false negative/positive reports. To reduce this bias, we referred to first-degree relatives also, whenever possible, to verify childhood and postnatal events. Moreover, some particular adverse life events may not be causally related to higher ADHD symptomatology, but some may be themselves triggered by more severe forms of ADHD (e.g., divorces, separation). However, the vast majority of adverse life events that were assessed focused on childhood or adolescence, thus limiting the chances of circular conclusions. Furthermore, stressors occurring in adulthood did not show a significant impact on ADHD symptomatology. It has to be also noticed that the impact of each adverse life event was not assessed by individual rating. Adverse life events such as severe childhood abuse may have caused substantially higher individual trauma than any other events (e.g., divorce of parents in late adolescence). In our study both events were rated equally but future studies should correct for subjective feelings of dismay and take these into account. Our sample was further characterized by a high rate of childhood and lifetime adverse events, but this is consistent with previous reports [Blanz et al., 1991; Allen et al., 1998; Cuffe et al., 2001; Counts et al., 2005], though some studies
The Serotonin Transporter and Life Events in Adult ADHD
reported a lesser impact of environmental factor on ADHD as compared, for example, to oppositional defiant disorder (ODD) [Ford et al., 1999; Rey et al., 2000]. Another limitation may be represented by sample selection: to avoid confounding effects, we did not include subjects with other predominating comorbid diagnosis possibly accounting for the ADHD symptoms; however this could reduce the representativeness of the sample. Finally, no consensus actually exists on diagnostic criteria for adult ADHD [McGough and Barkley, 2004]. The DSM criteria have not been validated in adults yet and seemed to fail identifying some significantly impaired adults [McGough and Barkley, 2004]. To overcome this issue we employed multiple self-report scales, which have been psychometrically evaluated and found valid and reliable as diagnostic aids for adult ADHD [Ward et al., 1993; Brown, 1996; Conners, 1999]. In conclusion, our findings suggest a role for both stressors and genetic factors in ADHD symptomatology and its persistence in adulthood. Consistently with previous findings, we confirm a role for the SERTPR*L allele in ADHD; on the other hand, our findings suggest the S allele as a moderator of environmental risk factors, similarly as it has been shown in depressive and anxious disorders. Nevertheless, given the above-mentioned limitations and the small significances detected, present findings have to be kept with cautiousness and more investigation is undeniably required. As a final point, the result of our study suggest the effectiveness of taking into account environmental factors in genetic studies, to resolve some of the inconsistent studies reported thus far in ADHD as well as other psychiatric disorders.
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ACKNOWLEDGMENTS The authors would like to acknowledge the valuable work done by Ruth Barton and Ramesh Shah in assisting the clinical assessment of the patients that participated in this study and Nicole King for their assistance in the laboratory procedure. This work was supported by a Canadian Institutes of Health Research (CIHR) operating grant to JLK and a CIHR postdoctoral fellowship award to DJM.
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