No association of the serotonin transporter polymorphisms 5‐HTTLPR and RS25531 with schizophrenia or neurocognition

Konneker, Thomas; Crowley, James J.; Quackenbush, Corey R.; Keefe, Richard S.E.; Perkins, Diana O.; Stroup, T. Scott; Lieberman, Jeffrey A.; Oord, Edwin van den; Sullivan, Patrick F.

doi:10.1002/ajmg.b.31077

Cited by 15 publications

(6 citation statements)

References 10 publications

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“…The ISC results do not implicate common genetic variation in these genes. Although the region containing SLC6A4 shows no signal, the widely-studied promoter polymorphism (HTTLPR) was not directly genotyped and neighboring SNPs are in low linkage disequilibrium (Konneker et al , in press). …”

Section: Resultsmentioning

confidence: 99%

Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results

Collins

Kim

Sklar³

et al. 2011

Psychol. Med.

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Background Candidate gene studies have been a key approach to the genetics of schizophrenia. Results of these studies have been confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised via comparison with the results of genome-wide association studies (GWAS). Methods We described the characteristics of hypothesis-driven candidate gene studies from SZGene, and used pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International Schizophrenia Consortium (ISC). Results SZGene contained 732 autosomal genes evaluated in 1,374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC had power of 89% to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISC p-values in hypothesis-driven candidate genes nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (schizophrenia as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes had no notable ISC results (COMT, DRD3, DRD2, HTR2A, NRG1, BDNF, DTNBP1, and SLC6A4). Conclusions We did not find support for the idea that the hypothesis-driven candidate genes studied in the literature were enriched for common variation involved in the etiology of schizophrenia. Larger samples are required definitively to evaluate this conclusion.

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Section: Resultsmentioning

confidence: 99%

Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results

Collins

Kim

Sklar³

et al. 2011

Psychol. Med.

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“…Studies of an association of 5 - HTTLPR with performance in the WCST yielded conflicting results with sometimes the S-allele [ 13 ] and sometimes l -homozygosity [ 14 ] being associated with better executive performance. Other recently published studies did not detect any associations between the 5 - HTT polymorphism and WM measures, specifically the Count Span task [ 8 ] and a WM summary score comprising a visuospatial WM task and LNS [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms of 5-HTT and DAT but not COMT differentially affect verbal and visuospatial working memory functioning

Zilles

Meyer

Schneider‐Axmann

et al. 2012

Eur Arch Psychiatry Clin Neurosci

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Working memory deficits are found in different psychiatric populations and are most pronounced in schizophrenia. There is preliminary evidence from pharmacological studies that the verbal and visuospatial subcomponents of working memory are subject to differential neurotransmitter modulation. Here, we investigated the impact of well-known polymorphisms of the dopamine transporter gene (SLC6A3, DAT) and the catechol-O-methyl-transferase gene (COMT) as well as the serotonin transporter gene (SLC6A4, 5-HTT) on these specific working memory subcomponents in a mixed sample of patients and healthy individuals. Twenty healthy subjects and 80 patients diagnosed with schizophrenia, bipolar I disorder, or obsessive-compulsive disorder underwent genotyping for the DAT variable number of tandem repeats (VNTR), the COMT val/met-, and the 5-HTT promoter length polymorphism (5-HTTLPR) and neuropsychological testing using a battery of well-characterized, brain circuit–specific working memory tasks. DAT genotype revealed a significant and selective effect on visuospatial working memory, while there was no effect on verbal working memory functioning. 5-HTT genotype, by contrast, exerted a significant and selective effect on verbal working memory task performance. COMT genotype did not show any influence on either working memory domain. The results of the present study provide evidence for a differential impact of genetic polymorphisms of the dopaminergic and serotonergic systems on verbal and visuospatial working memory functioning. Together with prior evidence suggesting the existence of subgroups of schizophrenia patients exhibiting isolated deficits in only one working memory domain, this finding further supports the idea of endophenotypically and pathophysiologically distinct subgroups of schizophrenia with implications for personalized therapeutic approaches.

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“…For further analyses and in analogy to preceding studies (e.g. Konneker et al, 2010;Klauke et al, 2011;Costafreda et al, 2013;Odgerel et al, 2013), 5-HTTLPR/rs25531 haplotypes were grouped according to functionality (high-activity L A /L A = 29 vs. low-activity 'rest': L G L G = 2, L A S A = 36, L A S G = 14, S A S A = 13), since the rs25531 G allele reportedly results in reduced transcription levels similar to those of the 5-HTTLPR S allele rendering only the A variant of the L allele (designated L A ) as yielding high 5-HTT mRNA levels (Hu et al, 2006;cf. Wendland et al, 2006).…”

Section: Genotyping Of 5-httlpr/rs25531mentioning

confidence: 92%

Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response

Domschke

Tidow

Schwarte

et al. 2014

Int. J. Neuropsychopharm.

152

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Variation in the serotonin transporter gene (5-HTT; SERT; SLC6A4) has been suggested to pharmacogenetically drive interindividual differences in antidepressant treatment response. In the present analysis, a 'pharmaco-epigenetic' approach was applied by investigating the influence of DNA methylation patterns in the 5-HTT transcriptional control region on antidepressant treatment response. Ninety-four patients of Caucasian descent with major depressive disorder (MDD) (f = 61) were analysed for DNA methylation status at nine CpG sites in the 5-HTT transcriptional control region upstream of exon 1A via direct sequencing of sodium bisulfite treated DNA extracted from blood cells. Patients were also genotyped for the functional 5-HTTLPR/rs25531 polymorphisms. Clinical response to treatment with escitalopram was assessed by intra-individual changes of HAM-D-21 scores after 6 wk of treatment. Lower average 5-HTT methylation across all nine CpGs was found to be associated with impaired antidepressant treatment response after 6 wk (p = 0.005). This effect was particularly conferred by one individual 5-HTT CpG site (CpG2 (GRCh37 build, NC_000017.10 28.563.102; p = 0.002). 5-HTTLPR/rs25531 haplotype was neither associated with 5-HTT DNA methylation nor treatment response. This analysis suggests that DNA hypomethylation of the 5-HTT transcriptional control region - possibly via increased serotonin transporter expression and consecutively decreased serotonin availability - might impair antidepressant treatment response in Caucasian patients with MDD. This pharmaco-epigenetic approach could eventually aid in establishing epigenetic biomarkers of treatment response and thereby a more personalized treatment of MDD.

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No association of the serotonin transporter polymorphisms 5‐HTTLPR and RS25531 with schizophrenia or neurocognition

Cited by 15 publications

References 10 publications

Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results

Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results

Genetic polymorphisms of 5-HTT and DAT but not COMT differentially affect verbal and visuospatial working memory functioning

Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response

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