Research paper
Environmental and genetic determinants of childhood depression: The roles of DAT1 and the antenatal environment

https://doi.org/10.1016/j.jad.2016.03.023Get rights and content

Highlights

  • A SNP from the DAT1 gene interacted with measures of early life stress to influence depressive symptoms in children.

  • SGA and a SNP from the dopamine transporter gene DAT1 had an interactive effect on children's depressive symptoms.

  • Depression symptoms were greater in children born SGA who are T homozygous for the rs1042098 SNP.

  • Adverse antenatal environments leading to low birth weight may exacerbate the effects of certain DAT1 variants on depression.

Abstract

Research on adolescent and adult populations has linked depression to variation in several monoaminergic genes, but genetic association studies on depression in children are limited. Additionally, few studies have investigated whether stressors occurring very early in development moderate the influence of certain genes on depression. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) from monoaminergic genes interacted with measures of early life stress to influence depressive symptoms in children. Participants were members of the Auckland Birthweight Collaborative cohort. Small for gestational age (SGA) and maternal stress during pregnancy were measured at birth and used as indicators of early life stress. At age 11, depressive symptoms were measured using the Centre for Epidemiological Studies Depression Scale for Children (CES-DC) and DNA samples were collected for genotyping. A two-way ANOVA revealed that SGA and a SNP from the dopamine transporter gene DAT1 had an interactive effect on children's depressive symptoms. Specifically, symptoms were greater in children born SGA who are T homozygous for the rs1042098 SNP. These findings suggest that adverse intrauterine environments leading to low birth weight also seem to exacerbate the effects of certain DAT1 variants on depression.

Introduction

Depression is a common psychiatric disorder characterised by several symptoms, including depressed mood, reduced feelings of pleasure, low energy, guilt, low self-worth, disturbed sleep and appetite as well as poor concentration (American Psychiatric Association, 2013). Individuals with depression also tend to exhibit several abnormal neurobiological symptoms, including deficiencies in monoaminergic neurotransmitters (Dailly et al., 2004, Elder and Mosack, 2011, Nutt, 2008). Although a diagnosis of major depressive disorder can imply that the condition is a categorical construct, perspectives have shifted to view depression as behaviour on the more extreme end of a naturally occurring continuum of emotion (Hankin et al., 2005). This change in perspective has allowed researchers to relate factors that contribute to depressive symptoms in clinical populations to symptoms in community populations, and vice versa.

Family and twin studies have found that both environmental and genetic effects contribute to depression (Rice et al., 2002, Sullivan et al., 2000). Research on the environmental determinants of depression has indicated that factors occurring from as early as the gestational period appear to be related to later affective problems. Antenatal maternal stress in particular has been linked to numerous adverse cognitive, behavioural and emotional outcomes in offspring, including depression (Beydoun and Saftlas, 2008; Slykerman et al., 2015). In a longitudinal study, Robinson et al. (2008) found that a greater number of stressful events experienced by mothers increased the risk of 2 year old children presenting internalising problems, characterised by withdrawn, anxious and depressed behaviours. A subsequent study on the same sample examined the association between antenatal maternal stress and emotional problems, but also included measures at 5, 8, 10 and 14 years (Robinson et al., 2011). The study found that more stressful events during pregnancy were associated with a greater incidence of internalising problems, even at the later ages in childhood.

Low birth weight (LBW, defined as birth weight less than 2500 g), often indicative of exposure to an adverse gestational environment as a result of poor maternal nutrition and health (Kramer, 1987), has also been linked to negative outcomes later in life, including depression (Hack et al., 1995, Lau et al., 2011, Mori et al., 2012). A study by Mallen et al. (2008) found that LBW increased the risk of depression, but not anxiety, in a sample of young adults. Looking specifically at depression in children, Pereira et al. (2012) found that small for gestational age (SGA) was associated with a greater prevalence in depression symptoms for 10–11 year old Brazilian children.

Studies investigating the genetic basis of depression have typically focused on monoaminergic genes, as a deficiency in monoamines, namely serotonin, dopamine and norepinephrine, have often been reported in those with major depression (Dailly et al., 2004, Elder and Mosack, 2011, Nutt, 2008). Studies interested in the role of serotonin generally focus on 5-HTTLPR, which is located on the promoter region of the serotonin transporter gene. Research has indicated that individuals with the short allele have a greater risk of depression when compared to those homozygous for the long allele, particularly in association with the experience of stressful life events (Caspi et al., 2003). Additionally, a longitudinal study by Jokela et al. (2007) has also linked the serotonin receptor gene, HTR2A, to depression. Specifically, the study found that C homozygotes of the T102C polymorphism had lower levels of depression than T allele carriers when they were exposed to greater maternal nurturance.

Genes affecting the regulation of dopamine and norepinephrine may also contribute to depression. Hayden et al. (2010) investigated the dopamine receptor gene DRD2 and found that variation in the rs1800497 single nucleotide polymorphism (SNP) was associated with anxious and depressive symptoms in very young children. The dopamine transporter gene DAT1 has also been associated with depression. In a study of adolescent males, Haeffel et al. (2008) found that when exposed to maternal rejection, individuals who were T homozygotes for the rs40184 SNP had a significantly greater risk of depression when compared to C allele carriers. Regarding genes related to norepinephrine regulation, the SLC6A2 gene coding for the norepinephrine transporter (NET) has been identified as a possible candidate gene in the development of depression (Dong et al., 2009). This has been supported in a case-control study by Haenisch et al. (2009), who found that variation in the rs5558 SNP of the SLC6A2 gene was associated with a differential risk for major depression.

Genes coding for enzymes involved in the breakdown of these monoamines have also been implicated as possible candidate genes for depression, including the monoamine oxidase A (MAOA) and catechol-O-methyl transferase (COMT) genes. The long allele of the variable number tandem repeat polymorphism in the promoter region of the MAOA gene, which codes for a more active form of the MAOA enzyme, was found to increase the risk of depression in only females from a German sample (Schulze et al., 2000). Similar findings were also demonstrated in a study by Yu et al. (2005) from a Chinese population. In general, results showed that the frequency of the high activity-related longer allele was significantly greater in the depressed group than in controls in both male and female participants, although the author suggests that gender differences may also be present. The existence of these gender effects is not surprising as the MAOA gene is located on the X sex chromosome (Lan et al., 1989). Regarding the COMT gene, Met allele carriers of the functional Val158Met (rs4680) polymorphism have been associated with a greater risk of depression relative to the high activity Val carriers (Ohara et al., 1998). This is consistent with other reports that Val carriers show more efficient emotional processing (Mier et al., 2010).

The foetal programming hypothesis postulates that exposure to certain nutrients and chemicals in the intrauterine environment during critical periods of development can affect the growth and later development of the child (Beydoun and Saftlas, 2008). One way in which foetal programming may act is through an effect on the expression and function of genes. However, there is a dearth of studies that have assessed whether adverse gestational factors have programming effects on the regulation of monoaminergic neurotransmitters by interacting with associated depression susceptibility genes. In fact, gene-environment interaction studies on depression have generally focused on an interaction between monoaminergic genes (namely 5-HTTLPR, MAOA and dopamine transporter and receptor genes) and post-natal life stressors such as abuse, family adversity and victimization (e.g., Agnafors et al., 2013, Cutuli et al., 2013, Haeffel et al., 2008, Hayden et al., 2010, Jokela et al., 2007, Lavigne et al., 2013, Sugden et al., 2010).

Nevertheless, some studies have implied that monoaminergic genes and early life stressors, such as antenatal maternal stress, have interactive effects on later affective problems. Pluess et al. (2011) found that the presence of maternal anxiety during pregnancy interacted with the 5-HTTLPR polymorphism in its effect on the negative emotionality of offspring six months following birth. Specifically, infants of different genotypes only differed in negative emotionality when exposed to high maternal stress during pregnancy. A study on rats by Alonso et al. (1994) found that the transmission of dopamine in the brain, particularly in the nucleus accumbens, was altered in offspring when they were exposed to maternal stress during pregnancy. Thus, it is possible that antenatal maternal stress may also interact with genes related to the regulation of dopamine to influence depression.

As noted above, SGA can also be indicative of an adverse prenatal environment (Kramer, 1987). Additionally, there is evidence that birth weight may interact with genetic factors to influence depressive symptoms (Rice, Harold, and Thapar, 2006). A twin study by Rice et al. (2006) found that an increased risk for depression associated with being born SGA was greater if individuals also had a genetic risk for depression. However, interaction studies between birth weight and specific genes on depression have yet to be investigated. Nevertheless, Thapar et al. (2005) found that the Val158Met polymorphism of the COMT gene interacted with birth weight in children with attention deficit hyperactivity disorder (ADHD) to predict the early onset of conduct problems, with LBW Val homozygotes showing a greater susceptibility to developing antisocial behaviours in the presence of low birth weight. Although this study was related to a different psychiatric problem, it does indicate that LBW can interact with genetic susceptibility to influence subsequent developmental outcomes. It is possible that LBW may be a marker of poor intrauterine environment, either due to antenatal maternal stress or other factors and may, in the presence of certain genetic susceptibility variants, lead to increased risk of behavioural and emotional problems, such as depression, later in life.

Research on the environmental and genetic determinants of depression has indicated that early life stressors and monoaminergic genetic variants may be associated with depression and depressive symptoms. However, few studies have investigated whether these factors have interactive effects on depression. It is also important to note that research looking at the interaction between genetic and environmental factors on depression have generally focused on adolescent or adult populations. Thus, in the current study we investigated whether environmental factors, specifically indicators of early life stressors such as SGA and antenatal maternal stress, moderated the influence of certain SNPs on depressive symptoms in 11 year old children. SNPs from several monoaminergic genes, specifically the HTR2A, DRD2, DAT1, SLC6A2, MAOA and COMT genes, were investigated.

Section snippets

Participants

Participants of the current study were members of the longitudinal Auckland Birthweight Collaborative (ABC) cohort. A detailed description of the ABC study is provided in Thompson et al. (2001). In brief, from 16 October 1995–12 August 1996, babies born in the Waitemata Health Region and Auckland Healthcare Region were eligible for inclusion in the study. Maternal obstetric information, which was necessary for consenting participants, was no longer available for mothers born in the Waitemata

Results

Mean depression scores were 11.64 points (SD=8.41; skewness=1.32, SE=0.16) for children who experienced high antenatal maternal stress, and 9.69 points (SD=6.94; skewness=1.42, SE=0.12) for children exposed to low levels of antenatal maternal stress. The AGA group had a mean depression score of 10.12 points (SD=7.27; skewness=1.42; 0.13), whereas the SGA group had an average depression score of 10.79 points (SD=7.94; skewness=1.41, SE=0.15), see Table 1.

Discussion

The present study's aim was to determine whether SNPs from monoaminergic genes interacted with either antenatal maternal stress or birth weight to influence depressive symptoms in childhood. Results revealed that the rs1042098 SNP on the DAT1 gene was related to depressive symptoms, and this effect was moderated by birth weight but not antenatal maternal stress. T homozygotes of the rs1042098 SNP who were born SGA had average depression scores that were 3.58 points greater than that of C allele

Acknowledgements

The ABC study group also includes Mrs Elizabeth Robinson, Dr David Becroft and Professor Chris Wild. We acknowledge the assistance of Gail Gillies, Barbara Rotherham, and Helen Nagels for contacting or assessing the participants.

The Health Research Council of New Zealand funded the initial study. The 12 month postal questionnaire was funded by the Hawkes Bay Medical Research Foundation. The 3.5 year follow-up phase was funded by the Cure Kids (previously Child Health Research Foundation),

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