Molecular genetics of obsessive–compulsive disorder: a comprehensive meta-analysis of genetic association studies

Molecular genetics of obsessive-compulsive disorder: a comprehensive meta-analysis of genetic association studies.

Combining genetic and epigenetic parameters of the serotonin transporter gene in obsessive-compulsive disorder

Trio study and meta-analysis support the association of genetic variation at the serotonin transporter with early-onset obsessive–compulsive disorder

The serotonin transporter is a key regulator of the bioavailability of serotonin and therefore any modulation in the expression or action of the transporter would be expected to have consequences on behaviour. The transporter has therefore become a target for pharmaceutical intervention in behavioural and mood disorders. The search for polymorphic variants in the transporter that would associate with neurological disorders has been extensive but has become focused on two domains which are both termed variable number tandem repeat (VNTR) polymorphisms. Both of these VNTRs are in non-coding DNA and therefore proposed to be mechanistically involved in a disorder through their ability to modulate transcriptional or post-transcriptional regulation of the transporter. The most extensively studied is in the promoter and is a bi-allelic insertion/deletion found in the 5′ promoter region of the gene 1.2 kb upstream of the transcriptional start site. This VNTR, termed, 5-HTTLPR was initially identified as two variants containing either, 14 (short/deletion) or 16 (long/insertion) copies of a 22 bp repeat. A second widely studied VNTR found in the non-coding region of the transporter is located within intron 2 and comprises 9, 10 or 12 copies of a 16–17 bp repeat termed, STin2.9, STin2.10 and STin2.12, respectively. These VNTR polymorphisms have been associated with a range of behavioural and psychiatric disorders including depression, OCD, anxiety and schizophrenia, however often the lack of reproducibility in different cohorts has led to debate on the actual association of the polymorphisms with this extensive range of neurological conditions. Here we review these two polymorphic VNTRs in depth and relate that to pharmaceutical response, their ability to regulate differential transporter expression, their core involvement in gene-environment interaction and their genetic association with specific disorders.

Behavioural Genetics of the Serotonin Transporter

Though still in infancy, the field of psychiatric genetics holds great potential to contribute to the development of new diagnostic and therapeutic options to treat these disorders. Among a large number of existing neurotransmitter systems, the serotonin system dysfunction has been implicated in many psychiatric disorders and therapeutic efficacy of many drugs is also thought to be based on modulation of serotonin. Serotonin transporter gene polymorphism is one of the most extensively studied polymorphisms in psychiatric behavioral genetics. In this article, we review the status of evidence for association between the serotonin gene polymorphism and some common mental disorders like affective disorders, post-traumatic stress disorder, obsessive-compulsive disorder, suicide, autism, and other anxiety and personality disorders. Going beyond traditional association studies, gene-environment interaction, currently gaining momentum, is also discussed in the review. While the existing information of psychiatric genetics is inadequate for putting into practice genetic testing in the diagnostic work-up of the psychiatric patient, if consistent in future research attempts, such results can be of great help to improve the clinical care of a vast majority of patients suffering from such disorders.

Serotonin transporter gene polymorphism and psychiatric disorders: is there a link?

Background and Objectives : Serotonin transporter polymorphisms, 5-HTTVNTR and 5-HTTLPR, have been found to be associated with obsessive-compulsive disorder (OCD) and particularly with neurotic characteristics. In the present study we looked for an association between OCD and these polymorphisms in OCD patients and controls of south Indian origin. Methods: 5-HTTVNTR and 5-HTTLPR/rs25531 were genotyped in 93 OCD patients and 92 healthy controls. The allelic distribution and genotype frequency in cases and controls were compared using chi square test. In order to test for the effects of genotype on heterogeneity of the illness, linear regression analysis was undertaken for co-morbid depression status and YBOCS score (severity index). Results: There was no significant association with the 5-HTTVNTR or the 5-HTTLPR polymorphism. No significant association of OCD with the 5-HTTLPR genotype was found even on inclusion of the rs25531 locus, which is part of the transcription factor binding site as reported in earlier studies. However, severity of the illness showed a modest association with the dominant model. Interpretation and Conclusions : Our data show that genetic variation in the SLC6A4 gene regulatory region may not have a significant effect on OCD in the present population. Further replication in a large and independent cohort with an equal number of female subjects would help to ascertain if the absence of association in this cohort is due to the nullifying effect of the larger proportion of male subjects in our sample population. The marginal effect of the 5-HTTLPR (A/G) genotype obtained on linear regression with disease severity is suggestive of a potential role for this locus in the disease process.

Association of serotonin transporter gene polymorphisms with obsessive-compulsive disorder (OCD) in a South Indian population

Background: Genetic correlates of diseases of complex inheritance may include variations in several genes lying within a network of linked biological processes. Synaptic mechanisms, such as serotonin neurotransmission and second (third) messengers (e.g., glycogen synthase kinase [GSK]), have been implicated in susceptibility to mood disorders, the actions of therapeutic drugs and manipulation of circadian rhythms. A better understanding of such gene networks may be useful to understand the biology and treatment of mood disorders. Methods: We studied the association between serotonergic and GSK-mediated signaling networks with bipolar affective disorder (BPAD). We analyzed two single nucleotide polymorphisms (SNPs) in the HTR2A gene, a promoter SNP in SLC6A4 and a promoter SNP in the GSK3B gene in BPAD individuals and matched controls. A multifactor dimensionality reduction tool was employed to study gene–gene interactions and analyze multilocus genotype combination associations with high- or low-risk of B...

Identification of interaction between serotonin transporter and glycogen synthase kinase-3β gene polymorphisms: role in susceptibility to bipolar disorder

Objective: Descriptive study focused on SARS-COV-2 exposed neonates admitted to a tertiary center Neonatal Intensive Care Unit (NICU). Study design: Longitudinal cohort retrospective study of neonates admitted to a tertiary center NICU during March to August 2020. Key indices (risk factors) are described for exposed neonates in order to draw conclusions for preventive strategies. Findings: There were 459 deliveries during the study period. 177(12%) mothers tested positive for SARS-CoV-2 with 184 SARS-COV-2 exposed (exposed) neonates born to these mothers. Sixty exposed neonates (33%) were admitted to the NICU. Exposure was associated with prematurity (55%) and Low birth weight (40%). There were a high proportion of twin births in the cohort (23%). In comparison to exposed neonates who roomed in with their mothers, NICU neonates were four times (3.3% versus 0.8% respectively) more likely to test positive for SARS-COV-2. Exposed neonates were more likely to be born to women on public insurance, a measure of low socio-economic status. Conclusion: Maternal COVID-19, is associated with preterm births, and low birth weight. Infants of women on public insurance were more likely to be exposed. COVID preventive measures targeting pregnant women including vaccination will help protect newborns. Women on public insurance may require targeted outreach efforts to promote equitable uptake of preventive measures including COVID-19 vaccine. More studies are needed to define long term effect on exposed infants especially those with potentially synergistic risk factors like prematurity and low birth weight.

D. Subhashree

Papers

Association of serotonin transporter gene polymorphisms with obsessive-compulsive disorder (OCD) in a South Indian population

Identification of interaction between serotonin transporter and glycogen synthase kinase-3β gene polymorphisms: role in susceptibility to bipolar disorder

Epidemiologic Characteristics of COVID-19 Exposure in Neonates Admitted to the Neonatal Intensive Care Unit