Original articleSerotonin transporter and GABA(A) alpha 6 receptor variants are associated with neuroticism
Section snippets
Subjects
The 242 female and 177 male subjects are from 257 families participating in the Family Blood Pressure Program at the Tecumseh, Michigan Site (Thiel et al 2003). Subjects gave informed consent, and the study has been approved by the University of Michigan Medical School institutional review board. Ninety-nine percent of the subjects are non-Hispanic Caucasians. Family eligibility in this study required an available proband between 25 and 40 years of age with a systolic blood pressure in the
Results
We determined genotypes for 419 subjects at the 5-HTTLPR polymorphic site. Allele frequencies in this sample (adjusted for familial correlations) were s = .42 and l = .58. These frequencies are consistent with reported values for samples with similar ethnic compositions: s = .45; l = .55 (Lesch et al 1996).
In this sample, presence of the short allele is associated with a significantly higher mean neuroticism score (p = .004). In addition, the presence of the l allele was associated with lower
Discussion
This study represents the first large-scale replication of the association between 5-HTTLPR and neuroticism described by a group other than Lesch et al (1996). In our sample, 5-HTTLPR accounts for 2%–3% of the overall variance and 4%–5% of the genetic variance in neuroticism score. This is a smaller effect size than Lesch et al (1996) found in the original study (overall variance: 3%–4%; genetic variance: 7%–9%), consistent with the finding that original reports of an association tend to
Acknowledgements
This work was supported by the Nancy Pritzker Depression Research Network (RN, MB), the Michigan Society of Fellows (SS), the University of Michigan Medical Scientist Training Program Training Grant GM007863 (SS). Recruitment and DNA acquisition for the Tecumseh study was funded by National Heart Lung and Blood Institute Grant HL054512 (LG, AW).
We thank all the families who participated in the studies; Li Sheng, Goncalo Abecasis, Bonnie Theil, Nicholas Schork, and Maria Carolina Delgado for
References (37)
- et al.
A general test of association for quantitative traits in nuclear families
Am J Hum Genet
(2000) - et al.
GABAergic interneuronsImplications for understanding schizophrenia and bipolar disorder
Neuropsychopharmacology
(2001) - et al.
Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims
Biol Psychiatry
(1999) - et al.
NeuroticismA vulnerability marker for depression evidence from a family study
J Affect Disord
(1995) - et al.
Serotonin transporter and seasonal variation in blood serotonin in families with obsessive-compulsive disorder
Neuropsychopharmacology
(1998) GABA and mood disordersA brief review and hypothesis
J Affect Disord
(1995)- et al.
Use of unlinked genetic markers to detect population stratification in association studies
Am J Hum Genet
(1999) - et al.
Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha 6 receptors and the serotonin transporter in the level of response to alcoholA pilot study
Biol Psychiatry
(1999) - et al.
A genome-wide linkage analysis investigating the determinants of blood pressure in whites and African Americans
Am J Hypertens
(2003) - et al.
Pedigree tests of transmission disequilibrium
Eur J Hum Genet
(2000)
Personality in adulthoodA six-year longitudinal study of self-reports and spouse ratings on the NEO Personality Inventory
J Pers Soc Psychol
Stability and change in personality assessmentThe revised NEO Personality Inventory in the year 2000
J Pers Assess
Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism
Mol Psychiatry
Serotonin transporter protein gene polymorphism and personality measures in African American and European American subjects
Am J Psychiatry
Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample
Am J Med Genet
Role of the serotonin transporter gene in temperament and character
J Personal Disord
Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene
J Neural Transm Gen Sect
Serotonergic dysfunction, negative mood states, and response to alcohol
Alcohol Clin Exp Res
Cited by (115)
Trait anxiety, a personality risk factor associated with Alzheimer's Disease
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :These controversial findings may predict complex interactions between norepinephrine and AD pathologies. Given the role of the GABAergic system in anxiety (Möhler, 2012; Nuss, 2015), it is not surprising that polymorphisms in genes that regulate GABA synthesis or signaling have been reported to contribute to individual differences in trait anxiety (Sen et al., 2004; Bloss et al., 2011; Lacerda-Pinheiro et al., 2014). For example, an intronic SNP (rs17536211) in GABA type A receptor subunit γ1 (GABRG1) was associated with trait anxiety (Bloss et al., 2011).
High anxiety trait: A vulnerable phenotype for stress-induced depression
2018, Neuroscience and Biobehavioral ReviewsCitation Excerpt :The short allele leads to the synthesis of less 5-HTT protein than the long one, leading to higher serotonin concentration in the synaptic cleft (Canli and Lesch, 2007). Notably, the lower expressing 5-HTTLPR short variant allele was found to be associated with trait anxiety in various human studies (Greenberg et al., 2000; Kuhnen et al., 2013; Lesch et al., 1996; Minelli et al., 2011; Munafò et al., 2009b; Schinka et al., 2004; Sen et al., 2004a, 2004b; Zhang et al., 2015). Although most studies focused on adult populations, some studies also reported associations of the 5-HTTLPR short variant allele with increased shyness and inhibited temperament in children (Battaglia et al., 2005; Davies et al., 2013; Hayden et al., 2007) and in a rhesus monkey model for inhibited temperament (Bethea et al., 2004).
Mood disorders
2015, Handbook of Clinical NeurologyCitation Excerpt :The frequency of mood disorders, however, did not differ between patients with and without APOE-ɛ4 allele (Koponen et al., 2004). Polymorphisms in genes coding for proteins involved in the regulation of ascending aminergic systems and of the hypothalamus–pituitary–adrenal axis (e.g., 5HTT-P, tryptophan hydroxylase, MAO, COMT, FKBP5) and the interactions between genetic polymorphisms and environmental influences (Caspi et al., 2003) might play a role in the likelihood of developing mood disorders (Patkar et al., 2002; Arango et al., 2003; Zubenko et al., 2003; Binder et al., 2004; Lotrich and Pollock, 2004; Sen et al., 2004; Smith et al., 2004; Sun et al., 2004; Tunbridge et al., 2004; Lasky-Su et al., 2005). Genetic variations in central dopaminergic pathways can affect prefrontal function following traumatic brain injury (Lipsky et al., 2005; McAllister et al., 2008) and this can result in a faulty modulation of emotional responses.
Are there depression and anxiety genetic markers and mutations? A systematic review
2014, Journal of Affective DisordersCitation Excerpt :The GABRA6 is involved in several factors that contribute to anxiety disorder. Sen et al. (Pham et al., 2009; Sen et al., 2004) reported an association between a polymorphism of GABRA6 receptor and neuroticism, a personality trait related to anxiety and depression. GABRA6 variation has also been associated with increased production of cortisol and an increase in blood pressure in response to psychological stress (Pham et al., 2009; Uhart et al., 2004).