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Letter to the Editor   |    
Dr. Turecki and Colleagues Reply
GUSTAVO TURECKI, M.D., PH.D.; RICHARD BRIÈRE, PH.D.; KAREN DEWAR, PH.D.; ALAIN LESAGE, M.D.; MONIQUE SÉGUIN, PH.D.; NADIA CHAWKY, M.SC.; CLAUDE VANIER, M.D.; MARTIN ALDA, M.D.; RIDHA JOOBER, M.D.; CHAWKI BENKELFAT, M.D.; GUY A. ROULEAU, M.D., PH.D.
Am J Psychiatry 2000;157:1710-a-1711. doi:10.1176/appi.ajp.157.10.1710-a

To the Editor: In his letter Dr. Harrison points out the discrepancies between our findings—which suggested a relationship between variation in the 5-HT2A receptor gene (5HTR2A) and the level of [3H]ketanserin 5-HT2A receptor binding in the prefrontal cortex—and two other studies by authors who failed to observe such a relationship. A possible explanation for this inconsistency may be related to the characteristics of the patients included in our study, who were of French Canadian origin.

The existence of a founder effect in the French Canadian population has been confirmed by many studies (1). The French Canadian population currently living in Quebec is descended from approximately 7,000 founding individuals who came to "Nouvelle France" before 1760 (2). Because this is a relatively young population (approximately 12 generations), the background linkage disequilibrium is considerable. For instance, studies of unrelated subjects who carry a mutation for oculopharyngeal muscular dystrophy suggest that for a 5-centimorgan interval, 75% of the subjects of French Canadian origin share all alleles (3). These findings have been replicated in analyses conducted with different diseases (4).

Dr. Harrison reminds the reader that the polymorphisms used to investigate genetic variation in our study (and others) are of unknown function. Indeed, the T102C marker is a silent T→C base substitution (5), and the variants at the A-1438G locus present similar basal promoter activity (6). Therefore, it is possible that our positive results with the 5HTR2A polymorphisms investigated may in fact be a consequence of underlying linkage disequilibrium between these markers and a functional genetic variant located in a different coding or regulatory region of the 5HTR2A gene. Furthermore, because of the extent of the linkage disequilibrium observed in French Canadians, this functional variant could be located relatively far from the tested polymorphisms (regulatory sequences and enhancers). If this is the case, the other studies may have failed to detect such an effect because, although testing larger samples, they investigated patients selected from nonisolated, panmictic populations, in which the power to detect associations due to linkage disequilibrium is considerably reduced. Certainly, other explanations may be also proposed for the reported inconsistency. Among these are type I error and the different analytical procedures employed. To better understand these issues, we are in the process of collecting a larger and independent sample of French Canadian suicide cases and will attempt to replicate our previous findings.

Heyer E, Tremblay M: Variability of the genetic contribution of Quebec population founders associated to some deleterious genes. Am J Hum Genet  1995; 56:970–978
[PubMed]
 
Desjardins B: Homogeneite ethnique de la population quebecoise sous le regime francais. Cahiers Québecois de Démographie  1990; 19:63–76
 
Brais B, Bouchard JP, Xie YG, Rochefort DL, Chretien N, Tome FM, Lafreniere RG, Rommens JM, Uyama E, Nohira O, Blumen S, Korczyn AD, Heutink P, Mathieu J, Duranceau A, Codere F, Fardeau M, Rouleau GA: Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet  1998; 18:164–167; erratum 19:404
[PubMed]
[CrossRef]
 
Kibar Z, Der Kaloustian VM, Brais B, Hani V, Fraser FC, Rouleau GA: The gene responsible for Clouston hidrotic ectodermal dysplasia maps to the pericentromeric region of chromosome 13q. Hum Mol Genet  1996; 5:543–547
[PubMed]
[CrossRef]
 
Warren JT Jr, Peacock ML, Rodriguez LC, Fink JK: An MspI polymorphism in the human serotonin receptor gene (HTR2): detection by DGGE and RFLP analysis. Hum Mol Genet  1993; 2:338
 
Spurlock G, Heils A, Holmans P, Williams J, D’Souza UM, Cardno A, Murphy KC, Jones L, Buckland PR, McGuffin P, Lesch KP, Owen MJ: A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter. Mol Psychiatry  1998; 3:42–49
[PubMed]
[CrossRef]
 
+

References

Heyer E, Tremblay M: Variability of the genetic contribution of Quebec population founders associated to some deleterious genes. Am J Hum Genet  1995; 56:970–978
[PubMed]
 
Desjardins B: Homogeneite ethnique de la population quebecoise sous le regime francais. Cahiers Québecois de Démographie  1990; 19:63–76
 
Brais B, Bouchard JP, Xie YG, Rochefort DL, Chretien N, Tome FM, Lafreniere RG, Rommens JM, Uyama E, Nohira O, Blumen S, Korczyn AD, Heutink P, Mathieu J, Duranceau A, Codere F, Fardeau M, Rouleau GA: Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet  1998; 18:164–167; erratum 19:404
[PubMed]
[CrossRef]
 
Kibar Z, Der Kaloustian VM, Brais B, Hani V, Fraser FC, Rouleau GA: The gene responsible for Clouston hidrotic ectodermal dysplasia maps to the pericentromeric region of chromosome 13q. Hum Mol Genet  1996; 5:543–547
[PubMed]
[CrossRef]
 
Warren JT Jr, Peacock ML, Rodriguez LC, Fink JK: An MspI polymorphism in the human serotonin receptor gene (HTR2): detection by DGGE and RFLP analysis. Hum Mol Genet  1993; 2:338
 
Spurlock G, Heils A, Holmans P, Williams J, D’Souza UM, Cardno A, Murphy KC, Jones L, Buckland PR, McGuffin P, Lesch KP, Owen MJ: A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter. Mol Psychiatry  1998; 3:42–49
[PubMed]
[CrossRef]
 
+
+

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