Effect of a human serotonin 5-HT2A receptor gene polymorphism on impulsivity: Dependence on cholesterol levels

Journal of Affective Disorders 206 (2016) 23–30

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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Research paper

Effect of a human serotonin 5-HT2A receptor gene polymorphism on impulsivity: Dependence on cholesterol levels Katrin Tomson a,b, Mariliis Vaht a, Kariina Laas a, Toomas Veidebaum c, Jaanus Harro a,n a

Division of Neuropsychopharmacology, Department of Psychology, University of Tartu, Ravila 14A, Tartu, Estonia Department of Public Health, University of Tartu, Ravila 19, 50411 Tartu, Estonia c National Institute for Health Development, Hiiu 42, 11619 Tallinn, Estonia b

art ic l e i nf o

a b s t r a c t

Article history: Received 23 April 2016 Received in revised form 30 June 2016 Accepted 16 July 2016 Available online 19 July 2016

Background: Impulsivity is multidimensional: Low impulse control may result in behavioural disorders, but acting on the spur of moment may also be advantageous. Previous studies have shown negative associations between different facets of impulsivity and serotonergic function. Other investigations have found negative correlations between serum lipid levels and impulsivity. Methods: We have investigated whether the functional polymorphism -1438A/G in the serotonin 5-HT2A receptor gene (HTR2A) is associated with impulsivity levels and whether there is any interaction with serum lipid levels. This analysis was based on data of the population-representative Estonian Children Personality Behaviour and Health Study at age 25. Impulsivity was self-reported with the Adaptive and Maladaptive Impulsivity Scale. Results: Subjects with the A/A genotype of the HTR2A -1438A/G polymorphism had higher scores of Maladaptive impulsivity, but not Adaptive impulsivity. In females, high LDL and total cholesterol levels increased the genotype effect. In males, in the highest quartile of total or LDL cholesterol the genotype effect was altered, with G/G homozygotes having the highest Maladaptive impulsivity levels. Limitations: Only one cohort of the European Youth Heart Study (EYHS) was used in the current study and impulsivity measures were self-reported. Conclusions: Our results do not support the notion that low cholesterol levels universally lead to higher impulsivity, but it was found that high total and LDL cholesterol levels moderate the effect of the HTR2A gene promoter polymorphism. This suggests that future studies on impulsivity need to consider the interaction of serotonergic measures with the whole range of cholesterol levels. & 2016 Elsevier B.V. All rights reserved.

Keywords: Maladaptive Impulsivity HTR2A LDL Gender

1. Introduction Impulsivity is an essential feature of disruptive behaviour disorders (Dougherty et al., 1999), substance abuse (Allen et al., 1998; Brady et al., 1998), personality disorders (Mulder et al., 1999), bipolar disorder (Swann et al.,2001), and pathologically aggressive (Barratt et al., 1999) or suicidal behaviour (Corruble et al., 1999). Being a component of the initiation of any behaviour (Barratt and Patton, 1983; Evenden 1999) impulsivity can be disruptive in situations characterized by poor self-control and making decisions without forethought and regard for potential consequences (Dalley et al., 2011; Moeller et al., 2001). Yet, impulsivity also has a functional aspect. Dickman (1990) has differentiated functional n Correspondence to: Division of Neuropsychopharmacology, Department of Psychology, University of Tartu, Ravila 14A, Tartu 50411 Estonia. E-mail addresses: [email protected] (K. Tomson), [email protected] (M. Vaht), [email protected] (K. Laas), [email protected] (T. Veidebaum), [email protected] (J. Harro).

http://dx.doi.org/10.1016/j.jad.2016.07.036 0165-0327/& 2016 Elsevier B.V. All rights reserved.

and dysfunctional impulsivity, which both lead to fast and errorprone action but are different in essence. Functionally impulsive individuals make quick decisions according to situation, gaining from rapid action, dysfunctionally impulsive people on the other hand act with little forethought in non-reflective manner, in spite of negative consequences (Dickman, 1990). These two distinguishable types of impulsivity have also been confirmed by laboratory tests (Brunas-Wagstaff et al., 1995; Miller et al., 2004) and in animal studies (Dalley et al., 2007); they also contribute to different impulsivity profiles of distinct types of violations of law (Paaver et al., 2006). The heterogeneity of impulsivity is supported by studies on how various neurochemical systems, such as monoamine and cholinergic systems, control impulsive behaviour (Buckholtz et al., 2008; Canli, 2008; Reif et al., 2011). Although the neurochemistry of impulsivity is likely to imply several neurotransmitters, including dopamine, noradrenaline, endocannabinoids, and glutamate (Pattij and Vanderschuren, 2008), the pivotal role of brain serotonin (5-HT) has clearly emerged from many experimental

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K. Tomson et al. / Journal of Affective Disorders 206 (2016) 23–30

and clinical studies that have demonstrated an association between lower 5-HT transmission and high impulsivity (Brown et al., 1979, 1982; Carver and Miller, 2006; Kruesi et al., 1990; Linnoila et al., 1983; Paaver et al., 2007; Harro and Oreland, 2016). Experimental data have further supported this concept by altering impulsive performance with serotonergic manipulations (Cherek and Lane, 2000; Murphy et al., 2002; Nomura et al., 2006; Roy et al., 1988; Walderhaug et al., 2002). Further insights have emerged from the effects of selective 5-HT agonists and antagonists, which, respectively, exert inhibitory and excitatory effects on impulsivity in rats (Dalley and Roiser, 2012). Animal studies have reported that manipulation at the 5-HT2A receptor can affect impulse control. The 5-HT2A/2C agonist (7)-1(2,5-dimethoxy-4-iodophenyl)-2-aminopropan (DOI) administered systemically increases impulsivity in both reaction time and delay discounting tasks, an effect blocked by 5-HT2A antagonists (J. Evenden and Ryan, 1999; J.L. Evenden and Ryan, 1999; Hadamitzky et al., 2009; Koskinen et al., 2000). In another paradigm, a selective 5-HT2A antagonist M100907 dose-dependently reduced impulsivity in the five-choice serial-reaction time task (Fletcher et al., 2007; Winstanley et al., 2005). In humans, several polymorphic variants have been described in the HTR2A gene, among them the -1438A/G polymorphism in the promoter region (Chen et al., 1992). The individuals carrying the A allele of the -1438A/G polymorphism have a higher promoter activity and expression of the receptor gene than the G/G homozygotes, and may yield larger number of 5-HT2A receptors (Myers et al., 2007; Parsons et al., 2004). Indeed, the A allele has been shown to be associated with increased 5-HT2A receptor binding in post-mortem studies (Turecki et al., 1999). Several studies have demonstrated associations between the HTR2A -1438 A/G polymorphism and mental disorders that are characterized by impulsive behaviour (Collier et al., 1997; Nishiguchi et al., 2001; Preuss et al., 2001; Ricca et al., 2004; Nomura et al., 2006). For example, the A allele was reported to be associated with impulsive traits in alcohol dependent patients (Preuss et al., 2001) and with susceptibility to anorexia nervosa (Collier et al., 1997). It was also found that patients carrying the A allele who suffered either from anorexia nervosa or bulimia nervosa exhibited greater overall severity of the corresponding eating disorder (Nomura et al., 2006; Ricca et al., 2004). Another biological factor historically associated with impulsive behaviour is the cholesterol levels. For example, in a sample of 2051 healthy subjects with mean age 23 years it was found that people in the lowest tenth of the total cholesterol distribution scored significantly higher on the impulsivity scale (Pozzi et al., 2003). Significant negative correlations between the total serum cholesterol and self-reported scores of impulsivity were found also in 100 consecutive patients who had attempted suicide (Garland et al., 2000). However, only a small number of studies have focused on cholesterol fractions. Among them several have found a negative correlation between impulsivity, suicidal behaviour and low-density lipoprotein (LDL) cholesterol (Agargun et al., 2004; Garland et al., 2007; Lee and Kim, 2003). A similar association has been found between high-density lipoprotein (HDL) cholesterol and scores on the Barratt Impulsivity Scale (Buydens-Branchey et al., 2000). In contrast to these studies, Roy et al., (2001) found no significant correlation between total serum cholesterol levels and scores on the Barratt Impulsivity Scale in a sample of 168 patients. Several studies have suggested that serum cholesterol may be a marker for central serotonergic activity (Steegmans et al., 1996; Terao et al., 2000; Vevera et al., 2003). Experimentally decreasing the cholesterol content of cell membranes has been shown to reduce the binding affinity of a serotonin 5-HT1A and 5-HT7 receptor agonists as well as to alter G-protein coupling of the receptor

(Pucadyil and Chattopadhyay, 2004; Scanlon et al., 2001; Sjögren et al., 2006). According to the widely accepted theory of Engelberg (1992) low cholesterol levels decrease the available number of serotonin receptors via the altered microviscosity of plasma membranes. Serotonin pathways function as a behavioural restraint system that inhibits impulsive behaviour (Volavka, 2002). Alterations in cholesterol levels could hence affect complex behaviours related to impulsivity by modulating serotonergic mechanisms. In the present study we investigated the association of the HTR2A -1438A/G polymorphism with impulsivity traits with consideration of serum lipid levels in a population-representative sample.

2. Methods 2.1. Study population The sample was based on the older cohort of the European Youth Heart Study (EYHS) conducted in Estonia in 1998/99 (Harro et al., 2001), which was incorporated into the longitudinal Estonian Children Personality, Behaviour and Health Study (ECPBHS; Tomson et al., 2011). Data at the follow-up in 2008 were used. The total number of participants was 540: 230 men and 310 women. The mean age of the subjects at the follow-up was 24.7, SD¼ 0.7. The study was carried out in accordance with the Declaration of Helsinki and approved by the Ethics Review Committee on Human Research of the University of Tartu, Estonia. Informed consent was signed by each participant. 2.2. Impulsivity measures Different facets of impulsivity (Fast decision making, Excitement seeking, Disinhibition, Thoughtlessness) were self-reported using the Adaptive and Maladaptive Impulsivity Scale (AMIS; Laas et al., 2010). AMIS is an impulsivity questionnaire developed on the basis of the concept of Dickman (1990), drawing on both Dickman impulsivity inventory (Dickman, 1990) and the five-factor personality model (Costa and McCrae, 2010). Fast decision making and Excitement seeking were added to obtain a measure termed Adaptive impulsivity, while Disinhibition and Thoughtlessness formed the score of Maladaptive impulsivity. 2.3. Blood lipid measurements Fasting basal cholesterol ((total cholesterol (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL)), as well as triglyceride levels were measured by conventional techniques in the Central Laboratory of the Tartu University Hospital, and presented in mmol/l. 2.4. Genotyping of the HTR2A polymorphism DNA was extracted from whole blood samples using Qiagen QIAamp Mini kit. Genotyping of -1438A/G (rs6311) polymorphism was performed as previously (Maksimov et al., 2015) using the TaqMans Pre-Designed SNP Genotyping Assay on the Applied Biosystems ViiA™ 7 Real-Time PCR. 2.5. Data analysis Subjects were divided by HTR2A genotype into groups of A/A, A/G and G/G. Genotype frequencies were 12.2%, 42.4% and 45.4%, respectively. Analysis of variance (ANOVA) with Tukey's post hoc multiple comparison procedures were used to determine the associations between dependent variables (cholesterol levels or

K. Tomson et al. / Journal of Affective Disorders 206 (2016) 23–30

impulsivity measures) and the genotype. The associations between cholesterol levels and impulsivity traits were tested by regression analysis. To determine the interaction effects of genotype, sex and cholesterol levels on impulsivity traits, general liner models (GLM) were performed. In order to decrease the chance of Type I error, contrasts were computed only for statistically significant effects, using reduced models where non-significant terms were omitted. For descriptive purposes the total and LDL cholesterol levels were divided into 4 quartiles. All tests were controlled for gender effects. The level of significance was set at p o0.05 and where appropriate Bonferroni correction was used. Statistical analyses were carried out using the Statistica version 7.0 software.

3. Results We found that the HTR2A genotype had statistically significant main effects on Disinhibition, Thoughtlessness, and Maladaptive impulsivity: The A/A homozygotes had higher expression of these impulsivity traits (F(2, 503) ¼5.20, p ¼0.006; F(2, 503) ¼5.79, p ¼0.003; F(2, 503)¼ 6.30, p ¼0.002 respectively; Fig. 1). In contrast, there was no statistically significant genotype main effect on Fast decision making or Excitement seeking, and hence on Adaptive impulsivity. An interaction effect between gender and genotype on Disinhibition (F(2, 503) ¼3.64, p ¼0.03), Thoughtlessness (F(2, 503)¼3.67, p¼ 0.03) and Maladaptive impulsivity (F(2, 503) ¼ 3.84, p ¼0.02) was also detected. The lowest impulsivity scores were found in male A/G heterozygotes and female G/G homozygotes, and these groups were significantly different from the female A/A homozygotes who had the highest scores. According to the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (2002), 81% of the participants had desirable TC levels (o 5.2 mmol/l), 7% had borderline

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high levels (5.2–6.2 mmol/l), and 22% had high levels (46.2 mmol/l). In case of LDL cholesterol, 45% of the participants had optimal levels (o 2.6 mmol/l), 37% had near optimal levels (2.6–3.3 mmol/l), and 13% had borderline high levels (3.4– 4.1 mmol/l) and 5% had high or very high levels ( 44.9 mmol/l). Levels of LDL cholesterol were strongly correlated with TC levels (r ¼0.91) while the HDL cholesterol was not correlated with TC (r ¼0.09) or LDL cholesterol (r ¼  0.27). Cholesterol (TC, LDL and HDL cholesterol) and triglyceride levels were not different between genotypes, and not directly associated with either Adaptive or Maladaptive impulsivity measures (data not shown). The F statistics for terms in General Linear Models of HTR2A genotype, total and LDL cholesterol levels, gender and facets of impulsivity are presented in Table 1. To elaborate on the direction of the interactions, contrasts were computed for gender, cholesterol levels and genotypes and are presented in Table 2. Since there were no main or interaction effects on Fast decision making, Excitement Seeking or Adaptive impulsivity, these data are not included. Similarly, HDL cholesterol and triglycerides did not have any main or interaction effects on impulsivity levels (data not shown). LDL cholesterol and gender had an interaction effect on Disinhibition, Thoughtlessness and Maladaptive Impulsivity, while total cholesterol had an interaction effect with gender on Thoughtlessness and Maladaptive Impulsivity, but not on Disinhibition. Female gender and higher LDL or total cholesterol levels together had a positive (raising) interaction effect on impulsivity measures. Only for Maladaptive Impulsivity there was an interaction effect between genotype and gender. Genotype interaction effect with gender and LDL cholesterol levels was found for Disinhibition, Thoughtlessness and Maladaptive impulsivity. Total cholesterol had an interaction effect with genotype and gender in Thoughtlessness and Maladaptive Impulsivity. Contrast analysis indicated

Fig. 1. A–C. Association of the HTR2A genotype with impulsivity traits in males and females. Disinhibition (A) and Thoughtlessness (B) Are subscales of Maladaptive Inhibition (C). All Data Are expressed as Mean 7 SEM. A. np o 0.05 different from females with A/A genotype. B. #p o 0.01 different from males with A/G genotype. C. nn p o 0.01 different from females with A/A genotype.

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K. Tomson et al. / Journal of Affective Disorders 206 (2016) 23–30

Table 1 F statistics for terms in General Lineal Models measuring effects of gender, genotype, cholesterol (TC and LDL cholesterol) and their interaction effects on impulsivity traits. Gender Disinhibition F TC 1.59 F LDL 1.95 Thoughtlessness F TC 4.23n F LDL 6.14n Maladaptive impulsivity F TC 3.44 F LDL 4.71n

Genotype

Cholesterol

Gender  Genotype

Gender  Cholesterol

Genotype  Cholesterol

Gender  Genotype  Cholesterol

3.31n 5.25nn

2.47 1.56

2.12 2.85

2.79 3.97n

2.18 2.91

2.86 4.16n

2.58 4.15n

9.25nn 5.21n

2.84 2.82

4.45n 6.30n

1.55 2.27

3.31n 3.87n

3.30n 5.24nn

6.70nn 3.92n

3.02n 3.43n

4.42n 6.27n

2.06 2.80

3.73n 4.72nn

Degrees of freedom for all analyses were 462. n

po 0.05. p o0.01.

nn

Table 2 t statistics showing the association of HTR2A -1438A/G polymorphism, LDL and total cholesterol levels on aspects of impulsivity. Term Level of effect

Gender Cholesterol fraction Female Cholesterol

Disinhibition t TC  1.26 t LDL  1.40 Thoughtlessness t TC  2.06n t LDL  2.48n Maladaptive impulsivity t TC  1.85 t LDL  2.17n

Gender  Cholesterol fraction Cholesterol, Female

Genotype A/A

G/G

 1.57  1.25

2.53n 3.12nn

 2.21n  2.91nn 1.99n

 3.04nn  2.28n

2.10n 2.75nn

 1.02  1.47

2.11n 2.51n

 2.59nn  1.98n

2.55n 3.24nn

 1.76  2.39n

2.10n 2.50n

Gender  Genotype

Gender  Genotype  Cholesterol fraction

A/A, Female

A/A, Cholesterol, Female

G/G, Cholesterol, Female

2.44n

 2.82nn

1.91 1.61

 2.57n  2.74nn

2.22n 2.22n

 2.72nn  3.07nn

 2.16n  2.21n

G/G, Female

2.40n 2.58n

The table presents contrasts in General Lineal Models. The values refer to t tests for the respective contrasts. A/A is computed vs. A/G and G/G is computed vs. A/G genotypes. Contrasts for non-significant interactions were not computed. Degrees of freedom for all analyses were 462. n

po 0.05. p o0.01.

nn

Table 3 Descriptive statistics depicting different facets of impulsivity in first and fourth quartile of total and LDL cholesterol based on HTR2A genotype. Female

Male

A/A Disinhibition TC 1 TC 4 LDL 1 LDL 4 Thoughtlessness TC 1 TC 4 LDL 1 LDL 4 Maladaptive impulsivity TC 1 TC 4 LDL 1 LDL 4

A/G

G/G

A/A

A/G

G/G

19.57 20.44 17.70 20.33

7 5.83 7 3.50 7 4.83 7 3.93

18.31 18.37 17.76 18.41

7 3.86 7 5.40 7 3.88 7 3.94

16.82 15.86 16.76 17.32

73.73 74.14 73.72 74.36

19.67 13.83 23.50 15.70

7 3.06 7 3.25 7 0.71 7 5.60

17.00 16.00 17.86 16.57

7 4.64 7 3.97 7 4.87 7 4.18

16.08 17.63 16.84 17.59

73.10 74.30 73.93 74.54

16.86 18.56 16.20 19.00

7 4.14 7 7.11 7 3.79 7 8.15

17.40 18.04 16.13 18.50

7 4.70 7 5.10n 7 4.81 7 4.16

16.77 13.94 15.95 15.00

74.72 75.08 74.58 74.64

21.00 14.67 22.00 16.10

7 2.65 7 5.82 7 1.41 7 5.02

15.88 14.58 16.79 14.39

7 4.41 7 4.35 7 5.21 7 4.09nn

15.96 16.00 15.82 16.32

74.33 73.68 75.07 73.86

36.43 39.00 33.90 39.33

7 9.47 7 10.16n 7 7.52 7 11.48

35.71 36.41 33.89 36.91

7 7.82 7 9.58n 7 7.91 7 6.63

33.59 29.81 32.71 32.32

77.42 78.33 77.23 78.12

40.67 28.50 45.50 31.80

7 5.51 7 8.96 7 0.71 7 9.85

32.88 30.58 34.64 30.96

7 8.33 7 7.37 7 9.28 7 7.38

32.05 33.63 32.67 33.91

76.86 77.04 78.59 77.50

Impulsivity: means 7 SD. TC1o 4.1 mmol/l, TC4 45 mmol/l, LDL1o 2.26 mmol/l and LDL4 43.22 mmol/l. n

po 0.05, vs female G/G. p o0.05, vs female A/G.

nn

that female A/A homozygotes with high total or LDL cholesterol had higher impulsivity measures, but in female G/G homozygotes, high total or LDL cholesterol resulted in lower impulsivity

measures (Table 2). General Linear Models showed that gender, cholesterol and genotype all had significant interaction effect on impulsivity

K. Tomson et al. / Journal of Affective Disorders 206 (2016) 23–30

measures. For better interpretation of the results, impulsivity measures were divided in addition to gender and genotype according cholesterol quartiles. Data of the first (lowest) and fourth (highest) total and LDL cholesterol quartiles are presented in Table 3. In the lowest quartile there were no differences in impulsivity, but in the highest quartile of total cholesterol the female G/G homozygotes had the lowest Thoughtlessness and Maladaptive Impulsivity measures ((F(2, 118) ¼4.62, p¼ 0.02) and (F(2, 118) ¼6.19, p ¼0.02) respectively) and female A allele carriers had the highest measures. Only in highest quartile of LDL cholesterol, males with the A/G genotype had the lowest Thoughtlessness that was significantly different from the corresponding female group (F (2, 110) ¼ 4.58, p ¼0.02).

4. Discussion We have found that the A/A genotype of the HTR2A –1438A/G polymorphism expresses significantly higher Maladaptive, but not Adaptive impulsivity in a population-representative sample of over five hundred 25 year olds. High levels of impulsivity belong to the core symptoms of substance use disorder and attention-deficit hyperactivity disorder, and are associated with aggressive behaviour and suicide. A wide range of studies has shown a linkage between disinhibition and thoughtlessness and the serotonergic neurotransmission. Interestingly, the other side of the coin, a cognitive style characterized by fast decision making and excitement seeking, was not found associated with this genotype, supporting the notion by Dickman (1990) on distinct functional and dysfunctional components of impulsivity. Majority of the studies suggest that impulsivity is related to lower serotonergic capacity (Harro and Oreland, 2016). Highly impulsive subjects have diminished cortical metabolic response to pharmacological challenge with the serotonin releasing drug fenfluramine (Siever et al., 1999; Soloff et al., 2000). Diminished serotonergic regulation in prefrontal areas, especially orbital and medial prefrontal cortex might decrease response inhibition, increase impulsivity and aggression, and increase the risk of suicidal behaviour (Soloff et al., 2007). The A allele of the 5-HT2A receptor gene has been shown to correspond to a higher transcriptional activity in the reporter gene assay in cell cultures and to be associated with increased 5-HT2A receptor binding (Parsons et al., 2004; Turecki et al., 1999). Although only speculatively related to the present findings, it is conceivable that higher levels of 5-HT2A receptors are associated with lower presynaptic serotonergic output, and, in turn, maladaptive impulsivity. Indeed, post-mortem studies in suicide victims have demonstrated an increase in the number of post-synaptic 5-HT2A binding sites in prefrontal cortex (Mann et al., 1986). Cholesterol levels are related to impulsivity and may also reflect central serotonergic activity. Mechanisms underlying the association between cholesterol and serotonin activity have not yet become clear, however, it has been suggested that both high and low cholesterol levels may lead to lower serotoninergic activity (Papakostas et al., 2004). According to the most accepted theory lowered plasma cholesterol concentration might induce a decrease in brain cell membrane cholesterol that ultimately would result in a reduced serotonergic function (Engleberg, 1992). Decrease in plasma total cholesterol or LDL cholesterol may induce a relative increase in brain cell membrane fluidity, which increases presynaptic serotonin reuptake and decreases postsynaptic serotonin function (Diebold et al., 1998). On the other hand several mechanisms have been proposed to explain how high cholesterol levels could also lead to low serotonergic function. One mechanism that mediates the interconnection between cholesterol and serotonin involves lipid rafts,

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which serve as assembly platforms for signalling complexes (Becher et al., 2001). Cholesterol may influence the conformation and function of membrane-bound receptors by reducing neuronal membrane fluidity and increasing mechanical strength of the membranes. The rigidity of cholesterol-enriched membrane can disrupt the function of lipid rafts (Ohvo-Rekika et al., 2002). Cholesterol can influence serotonergic function also indirectly by binding tightly to transmembrane ion channels, enzymes and receptors (Haines, 2002). Also studies on hypercholesterolemic patients show lower serotonergic action through blunted serotonin mediated vasodilation in forearm arteries and lower platelet serotonin concentrations than in controls (Smith and Betteridge, 1997; Stroes et al., 1997). Elevated as well as low cholesterol levels should be associated with serotonergic dysfunction through different mechanisms. In the present study cholesterol levels did not have a main effect on impulsivity measures, but rather had complex interaction effect with the HTR2A genotype and gender where high cholesterol levels were associated with higher impulsivity measures. Thus, in females high LDL or total cholesterol levels increased the -1438A/G genotype effect, resulting in very high Maladaptive impulsivity, but in males high cholesterol levels lowered the effect of the A allele of the -1438A/G polymorphism and rather resulted in G/G homozygotes having high Maladaptive impulsivity levels. As described earlier, most of the studies have found a negative correlation between cholesterol levels and impulsivity, but this is not universal. A study conducted in Korean population revealed that not only low, but also high total and LDL cholesterol levels predicted an increased incidence of suicidal ideation in an elderly population (Kim et al., 2014). Additionally, a recent Finnish study of 448 depressed elderly participants found higher total and LDL cholesterol levels in subjects with suicidal behaviour (Koponen et al., 2015). Another Finnish study found that high cholesterol levels are associated with the level of violence in suicidal behaviour (Tanskanen et al., 2000). While impulsivity and suicidality are not completely overlapping traits, maladaptive impulsivity may occasionally lead to self-destructive behaviour. Several studies have already suggested that the relationship between cholesterol and psychological variables may be non-linear. For example, suicide risk has been found the highest in patients within the lowest cholesterol quartile (Golier et al., 1996; Lindberg et al., 1992). Using a similar cut-off point, Troisi (2011) found a highly significant difference in attentional impulsivity between participants with total cholesterol levels lower than 4.3 mmol/l and the rest of the sample, with low cholesterol associated with high impulsivity. However, across the entire range of cholesterol (2.8–7.6 mmol/l) only a weak linear correlation was found. In the study of Pozzi et al. (2003), the significant inverse association between total and HDL cholesterol with impulsivity rested completely on men in lowest tenth of total cholesterol (r3.7 mmol/l). In our study cholesterol was used as a continuous variable. No cut-off values emerged where effect on impulsivity would have been greater than in the rest of the sample. When impulsivity levels of people from first ( r3.8 mmol/l) and last quartiles (Z5.3 mmol/l) of cholesterol were compared no differences emerged. Studies on impulsivity and cholesterol levels have mainly focused on total cholesterol. From the few studies addressing the cholesterol fractions, it appears that low HDL cholesterol levels can be linked with impulsivity and low LDL levels with suicide and self-harm. For example the study by Pozzi et al. (2003) that also assessed LDL and HDL levels found that the lipid fractions related to impulse control in healthy subjects were the total and HDL cholesterol. In an Italian community-based sample, impulsivityrelated traits measured by the NEO-PI-R were associated with lower HDL cholesterol and higher triglycerides. Also a study in

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patients who exhibited aggression and problems in impulse control found only the HDL cholesterol levels to be significantly lower. The total and LDL cholesterol were also lower in these patients, but differences did not reach the conventional level of significance (Buydens-Branchey el al., 2000). Other studies have found total cholesterol and LDL cholesterol levels to be significantly lower in the group of patients who had experienced failed attempts of suicide or exhibited other self-injurious behaviour compared to non-suicidal psychiatric patients and normal controls (Agargun et al., 2004; Lee and Kim, 2003). Most recently a meta-analysis (Wu et al., 2015) screened 65 studies on suicides and cholesterol fractions and came to the conclusion that it is the low total and LDL cholesterol as well as triglyceride levels that predict suicidality within patient groups, while compared with the healthy controls the suicidal patients had significantly lower total, HDL and LDL cholesterol levels. In the present study total and LDL cholesterol were highly correlated and indeed both were linked to Maladaptive impulsivity but any such association was not present with HDL cholesterol. The HTR2A -1438A/G polymorphism effect was present in Maladaptive impulsivity in both genders. When looking at subscales, the effect on Disinhibition was found only in women and not in men, while in case of Thoughtlessness the effect was clearer in men. The role of gender in impulsivity levels can be linked with gender differences in central serotonergic function that have previously been described. For example in patients with borderline personality disorder the 5-HT2A receptor binding was greater in females than in men and only in female patients predicted the binding potential values impulsivity and aggression (Soloff et al., 2014). While differences between males and females can be explained by gender specific differences in serotonergic agonism, it is also possible that sex hormones may play a role (Moses et al., 2000). While the study by Troisi (2011) had women to men ratio was 2:1, many of the studies that have shown a negative correlation between cholesterol and impulsivity had only male subjects. In highest quartile of both total and LDL cholesterol the elevating effect of the A/A genotype was strengthened in females, but for the males in highest quartile of both total and LDL cholesterol carrying the A/A genotype resulted in lowering Maladaptive impulsivity measures compared to men with A/A genotype in lowest cholesterol quartile. This finding highlights the importance of gender in analysis of gene and behavioural interactions. While taking separately, higher total and LDL cholesterol levels, female gender and HTR2A -1438A/G polymorphism all lead to higher impulsivity measures. Yet, the complexity of the interaction is emphasized by the finding that, despite not being a statistically significant effect, male A/A homozygotes in the lowest quarter of total or LDL cholesterol had very high measures of Maladaptive impulsivity that would be compatible with the majority of findings in literature. The current study should be viewed with caution due to three limitations. Most importantly, we did not take into account other genetic factors, disorders or medications that could be interacting, acting as effect modifiers or confounders. Secondly only data of one cohort were used. Thirdly, impulsivity was only self-reported. While the use of self-report questionnaires is widely accepted, self-report scales do have their limitations and behavioural measures of impulsivity could offer added value.

5. Conclusion The main finding of the study is that A/A genotype of -1438A/G HTR2A polymorphism is associated with significantly higher Maladaptive, but not Adaptive impulsivity traits in both females and males in our population-representative sample of 25 year olds.

High LDL or total cholesterol levels in females increase the -1438A/ G genotype effect resulting in very high Maladaptive impulsivity. In males with highest quartile total or LDL cholesterol levels the genotype effect is modified with A allele carriers having lower Maladaptive impulsivity levels than G/G homozygotes. Since serum lipid levels, especially total and LDL cholesterol have an effect on serotonergic function, it is important not to underestimate their possible interaction with psychiatric disorders, in particular impulsivity and suicidality.

Role of funding source None.

Conflict of interest None.

Acknowledgements This study was supported by grants from the Estonian Ministry of Education and Science (IUT20-40 and IUT 42-2), European Regional Development Fund ERC Program TerVE (ELIKTU 3.2.10002.11-0002) and European Community Seventh Framework Programme under grant agreement no. 602805 (Aggressotype). We are grateful to the participants of the ECPBHS and to the whole ECPBHS Study Team. The authors declare that there are no conflicts of interest.

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