Serotonin transporter and GABA(A) alpha 6 receptor variants are associated with neuroticism

doi:10.1016/j.biopsych.2003.08.006

Biological Psychiatry

Volume 55, Issue 3, 1 February 2004, Pages 244-249

https://doi.org/10.1016/j.biopsych.2003.08.006 Get rights and content

Abstract

Background

A tendency to experience negative affect, as measured by the neuroticism component of the Neuroticism, Extraversion, and Openness Personality Inventory (NEO-PI), is a trait marker for major depression. Epidemiologic studies indicate a strong genetic component, but to date few specific genetic variants have been definitively implicated. A serotonin transporter promoter polymorphism (5-HTTLPR) has been extensively studied in neuroticism and several psychiatric disorders, with inconclusive results. A GABA(A) receptor α6 subunit variant (Pro385Ser) has been associated with alcohol-related traits but has not been studied in neuroticism or depression.

Methods

A total of 384 subjects who completed the NEO-PI were genotyped at 5-HTTLPR and Pro385Ser. Associations between polymorphisms and both alcohol use and personality domains were tested.

Results

The 5-HTTLPR short allele (p = .008) and Pro385Ser Pro allele (p = .003) are associated with higher neuroticism scores. The 5-HTTLPR long allele (p = .006), but not Pro385Ser, is also associated with an increased presence of alcohol use. In addition, there is a nonsignificant suggestion of an interaction: the effect of 5-HTTLPR on neuroticism might be dependent on the Pro385Ser genotype.

Conclusions

These findings support a role for the serotonin transporter and GABA(A) α6 subunit in depression-related traits.

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

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Original articleSerotonin transporter and GABA(A) alpha 6 receptor variants are associated with neuroticism

Abstract

Background

Methods

Results

Conclusions

Section snippets

Subjects

Results

Discussion

Acknowledgements

Am J Hum Genet

Neuropsychopharmacology

Biol Psychiatry

J Affect Disord

Neuropsychopharmacology

J Affect Disord

Am J Hum Genet

Biol Psychiatry

Am J Hypertens

Pedigree tests of transmission disequilibrium

Eur J Hum Genet

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

Original article
Serotonin transporter and GABA(A) alpha 6 receptor variants are associated with neuroticism