Indan Journal of Medical Research Indan Journal of Medical Research Indan Journal of Medical Research Indan Journal of Medical Research
  Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login  
  Home Print this page Email this page Small font sizeDefault font sizeIncrease font size Users Online: 1705       

   Table of Contents      
COMMENTARIES
Year : 2010  |  Volume : 132  |  Issue : 6  |  Page : 663-665

Serotonin transporter gene polymorphisms & obsessive-compulsive disorder


Servicios de Atención Psiquiátrica Minister of Health, Mexico

Date of Web Publication9-Apr-2011

Correspondence Address:
Humberto Nicolini
107, Carracci St. Col Extremadura Insurgentes
Mexico
Login to access the Email id

Source of Support: None, Conflict of Interest: None


PMID: 21245612

Rights and PermissionsRights and Permissions

How to cite this article:
Nicolini H. Serotonin transporter gene polymorphisms & obsessive-compulsive disorder. Indian J Med Res 2010;132:663-5

How to cite this URL:
Nicolini H. Serotonin transporter gene polymorphisms & obsessive-compulsive disorder. Indian J Med Res [serial online] 2010 [cited 2020 Apr 9];132:663-5. Available from: http://www.ijmr.org.in/text.asp?2010/132/6/663/75257

Obsessive compulsive disorder (OCD) is a neuropsychiatric condition that has been shown to be heritable and for which a major gene effect has been reported based on segregation studies [1],[2] . However, linkage analysis studies have not been able to confirm a locus for OCD [3] . The most promising candidate genes for OCD at the present time are in the serotonin system and the glutamate system [4] . The SCL6A4 gene has been the most extensively studied functional polymorphism in psychiatry, providing worldwide evidence of its importance in several disorders, such as OCD.

The efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of OCD has lead to the hypothesis of a serotonergic dysfunction in this disorder [5] . Since SSRIs acts on the serotonin (5HT) transporter (5HTT), it has been suggested that the 5HTT gene (SCL6A4), located on chromosome 17q12 [6] , could be a good candidate for OCD [7],[8],[9] . A functional polymorphism in the promoter region has been described [10] . This 5HTT-linked polymorphic region (5HTTLPR) is situated in a GC-rich region composed of 20-23 bp repeat units. The biallelic polymorphism consists of an insertion (long allele, "l") or a deletion (short allele, "s") of 44 bp. The serotonin transporter (SERT) is probably the most widely studied gene in psychiatry [11] . Previous studies have reported the "l" allele is as characterized by increased transcriptional activity as well as increased basal re-uptake of 5-HT in vitro compared with the short form of the 5HTTLPR [10] .

A possible association between 5HTTLPR polymorphism and OCD has been studied by some research groups. Billett et al[7] could not find an association in 72 OCD patients compared to 72 controls. However, a relative increase (not statistically significant) of homozygous ("l" allele) in the OCD group was observed. Bengel et al[8] , reported that OCD patients were more likely to carry two copies of the long allele ("l"), compared to controls. A study by McDougle et al[9] using a family-controlled transmission disequilibrium test (TDT), reported a predominant "l" allele transmission in 24 heterozygous parents to their OCD affected sibs. A preferred "l" allele transmission was also observed in 10 out of 13 SSRI non-responders. In addition, an analysis of SCL6A4 coding region has not revealed differences in OCD patients [12] . As suggested by these studies of a possible relationship between OCD and the "l" allele, our group analyzed the 5-HTTLPR polymorphism in Mexican OCD patients using a case-control methodology. Besides, we analyzed alternative methods that employ family-based sampling to minimize the effects of population heterogeneity in a sample of 43 trios [13] . Our results did not show a positive association between this variant and Mexican OCD patients. However, previous studies showed an association between OCD and "l" allele of 5-HTTLPR polymorphism, although the literature still remains controversial [8],[13],[14],[15] . In the case of Hu et al[14] , a single nucleotide polymorphism (SNP) that converts the long allele to a functionally short one was important in determining the significance of the SERT gene in OCD. The long allele containing the A variant of the SNP was associated with OCD, while the long-G and short alleles were not. Thus other groups should investigate this SNP in their analyses.

In addition, many association studies have resulted in controversial results because population stratification cannot easily be avoided [16] . Later studies showed that allele frequencies of the 5HTTLPR could vary widely between populations. The allele frequencies of our control group [13] were similar to Caucasian and European-American populations previously reported [8],[17] . These frequencies differ from those reported for Japanese and African-American subjects [18] . Since use of family-based approaches like TDT and HHRR may overcome ethnic stratification, analyzing a sample of trios for confirmation of an association between OCD and the SCL6A4 gene should always be performed. Family-based association analysis confirmed negative linkage disequilibrium between the 5HTTLPR polymorphism and OCD. TDT and HRR analysis did not reveal preferential "l" allele transmission. These studies did not support McDougle's initial hypothesis [9] that the "s" allele would be associated with increased susceptibility to OCD. This hypothesis was based on the report of an association between the "s" allele and neuroticism [17] and confirmed later in the susceptibility to depression in interaction with life events [19] . Neuroticism shares common genetic origins with affective and anxiety disorders, with each of many genes thought to contribute small amounts of variance [20] . Also, an association between 5HTTLPR and some disorders such as depression, life events and depression in psychosis and seasonal affective disorder and seasonality has been observed [21],[22],[23],[24] . All these findings, relating the "s" allele with some psychiatric disorders, may agree with the 5HT-anxiogenic theory and with the SSRI mechanism of action in these disorders as proposed by Lesch et al[17] . Moreover, if the expression of 5HTT is reduced in carriers of the "s" allele, the same dose of SSRI could increase synaptic 5-HT and induce desensitization of several postsynaptic 5-HT receptors. Since the evidence may support the hypothesis of a relationship between the "s" allele and anxiety-related personality traits, studies of phenotypes based on personality traits in OCD combined with the analysis of 5HTTLPR polymorphism may provide an important tool in disentangling genetic factors involved in the disorder. Extensive family-based studies combined with population genetic studies are needed, from large, and carefully collected samples using various phenotype definitions such as co-morbidity, age of onset, type of obsessions and compulsions, and personality an temperament dimensions among others before reaching a more definitive conclusion.

New evidence showing that some of the previous results may differ since the involvement of the 5HTTLPR (A/G) gene polymorphism modulating the 5HTTLPR, it may impose to new studies the need to assess this polymorphism. In addition, most association data come from case-control studies that do not assess population stratification instead of family based samples. The study presented in this issue by Tibrewal et al[25] , addresses both methodological concerns. It evaluates population stratification as well as the modulating 5HTTLPR (A/G) gene polymorphism. Due to small sample size it is difficult to see an effect of common genes of minor effects. Probably, some of the rare gene variants (CNVs) in these common alleles may have a larger effect in disease aetiology. However, it is intriguing to find a modest statistically significant association of the dominant model of 5HTTLPR (A/G) (non-risk allele: LA; risk alleles: SA, SG, LG) with the severity index or YBOCS score. These data may support the idea that the 5-HT system is altered in the brain of OCD patients depending upon severity. This sub-sample (including the ethnic component) may provide a great opportunity to further explore the contribution of rare variants by methods of deep sequencing. If the peripheral findings translate into the brain, increased 5-HT uptake or storage in the presynaptic terminal would be expected to diminish extracellular 5-HT availability. Unfortunately, a direct assessment of synaptic 5-HT in patients with OCD is not possible with present technologies. However, clinical pharmacological data may also provide additional phenotypes to better understand the participation of 5-HT in OCD genetic risk.

 
   References Top

1.Nestadt G, Lan T, Samuels J, Riddle M, Bienvenu OJ 3rd, Liang KY, et al. Complex segregation analysis provides compelling evidence for a major gene underlying obsessive-compulsive disorder and for heterogeneity by sex. Am J Hum Genet 2000; 67 : 1611-6.  Back to cited text no. 1
[PUBMED]  [FULLTEXT]  
2.Nicolini H, Hanna G, Baxter L Jr, Schwartz J, Weissbacker K, Spence MA. Segregation analysis of obsessive compulsive and associated disorders: Preliminary results. Ursus Medicus J 1991; 1 : 25-8.  Back to cited text no. 2
    
3.Shugart YY, Samuels J, Willour VL, Grados MA, Greenberg BD, Knowles JA, et al. Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q. Mol Psychiatry 2006; 11 : 763-70.  Back to cited text no. 3
[PUBMED]  [FULLTEXT]  
4.Nicolini H, Arnold P, Kennedy JL, Lanuzagorta N, Nedstadt G. Overview of genetics and obsessive compulsive disorder. J Psychiat Res 2009; 170 : 7-14.   Back to cited text no. 4
    
5.Barr LC, Goodman WK, Price LH. The serotonin hypothesis of obsessive compulsive disorder. Int Clin Psychopharmacol 1993; 8 (Suppl 2) : 79-82.  Back to cited text no. 5
[PUBMED]    
6.Gelernter J, Pakstis AJ, Kidds KK. Linkage mapping of serotonin transporter protein gene SLC6A4 on chromosome 17. Hum Genet 1995; 95 : 677-80.  Back to cited text no. 6
    
7.Billett EA, Richter MA, King N, Heils A, Lesch KP, Kennedy JL. Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene. Mol Psychiatry 1997; 2 : 403-6.  Back to cited text no. 7
[PUBMED]    
8.Bengel D, Greenberg BD, Cora-Locatelli G, Altemus M, Heils A, Li Q, et al. Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder. Mol Psychiatry 1999; 4 : 463-6.  Back to cited text no. 8
    
9.McDougle CJ, Epperson CN, Price LH, Gelernter J. Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. Mol Psychiatry 1998; 3 : 270-3.  Back to cited text no. 9
[PUBMED]    
10.Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996; 66 : 2621-4.  Back to cited text no. 10
    
11.Graff-Guerrero A, De la Fuente-Sandoval C, Camarena B, Gσmez-Martin D, Apiquian R, Fresαn A, et al. Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism. Neuroimage 2005; 25 : 197-204.  Back to cited text no. 11
    
12.Altemus M, Murphy DL, Greenberg B, Lesch KP. Intact coding region of the serotonin transporter gene in obsessive- compulsive disorder. Am J Med Genet 1996; 67 : 409-11.  Back to cited text no. 12
[PUBMED]    
13.Camarena B, Rinetti G, Cruz C, Hernandez S, de la Fuente JR, Nicolini H. Association study of the serotonin transporter gene polymorphism in obsessive-compulsive disorder. Int J Neuropsychopharmacol 2001; 4 : 269-72.   Back to cited text no. 13
    
14.Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, et al. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 2006; 78 : 815-26.  Back to cited text no. 14
[PUBMED]  [FULLTEXT]  
15.Meira-Lima I, Shavitt RG, Miguita K, Ikenaga E, Miguel EC, Vallada H. Association analysis of the catechol-o-methyltransferase (COMT), serotonin transporter (5-HTT) and serotonin 2A receptor (5HT2A) gene polymorphisms with obsessive-compulsive disorder. Genes Brain Behav 2004; 3 : 75-9.  Back to cited text no. 15
[PUBMED]  [FULLTEXT]  
16.Kinnear CJ, Niehaus DJ, Moolman-Smook JC, du Toit PL, Kradenberg J, Weyers JB, et al. Obsessive-compulsive disorder and the promoter region polymorphism (5-HTTLPR) in the serotonin transporter gene (SLC6A4): a negative association study in the Afrikaner population. Int J Neuropsychopharmacol 2000; 3 : 327-31.  Back to cited text no. 16
[PUBMED]  [FULLTEXT]  
17.Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274 : 1527-31.  Back to cited text no. 17
[PUBMED]  [FULLTEXT]  
18.Gelernter J, Kranzler H, Cubells JF. Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects. Hum Genet 1997; 101 : 243-6.  Back to cited text no. 18
[PUBMED]  [FULLTEXT]  
19.Caspi A, Sugden K, Moffitt T, Taylor A, Craig IW, Harrington H, et al. Influence on life stress on depression: moderation by a polymorphism in the 5HTT gene. Science 2003; 301: 386-9.  Back to cited text no. 19
    
20.Flory JD, Manuck SB, Ferrell RE, Dent KM, Peters DG, Muldoon MF. Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism. Mol Psychiatry 1999; 4 : 93-6.  Back to cited text no. 20
[PUBMED]    
21.Gutierrez B, Pintor L, Gasto C, Rosa A, Bertranpetit J, Vieta E, et al. Variability in the serotonin transporter gene and increased risk for major depression with melancholia. Hum Genet 1998; 103 : 319-22.  Back to cited text no. 21
    
22.Rosenthal NE, Mazzanti CM, Barnett RL, Hardin TA, Turner EH, Lam GK, et al. Role of serotonin transporter promoter repeat length polymorphism (5- HTTLPR) in seasonality and seasonal affective disorder. Mol Psychiatry 1998; 3 : 175-7.  Back to cited text no. 22
[PUBMED]    
23.Serretti A, Cusin C, Lattuada E, Di Bella D, Catalano M, Smeraldi E. Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders. Mol Psychiatry 1999; 4 : 280-3.  Back to cited text no. 23
[PUBMED]    
24.Contreras J, Hare L, Camarena B, Glahn D, Dassori A, Medina R, et al. The serotonin transporter 5-HTTPR polymorphism is associated with current and lifetime depression in persons with chronic psychotic disorders. Acta Psychiatr Scand 2009; 119 : 117-27.  Back to cited text no. 24
[PUBMED]  [FULLTEXT]  
25.Tibrewal P, Kiran Kumar HB, Shubha GN, Subhashree D, Purushottam M, Thennarasu K, et al. Association of serotonin transporter gene polymorphisms with obsessive-compulsive disorder (OCD) in a south Indian population. Indian J Med Res 2010; 132 : 690-5.  Back to cited text no. 25
    




 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    References

 Article Access Statistics
    Viewed557    
    Printed51    
    Emailed0    
    PDF Downloaded176    
    Comments [Add]    

Recommend this journal