type on platelet serotonin transporter functionality in de-pressed children and adolescents.J Am Acad Child Adolesc Psychiatry38:1396 –1402.
Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M (1998): Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine.Mol Psychiatry3:508 –511.
Reply
To the Editor:
Battaglia et al based their comments on the fact that in our article (Leboyer et al 1999b) “we did not make any genotyping of the 5-HTTLPR.” They further suggest that we should have selected the unaffected relatives on the basis of their 5-HTTLPR genotypes. This suggestion is highly inappropriate according to the strategy we are using, which is the identification of peripheral vulnerability markers (“endophenotypes”) in nonaffected rela-tives of psychiatric patients (Leboyer et al 1998, 1999a, 1999b; Pierson et al, in press). Endophenotypes are traits, or covariates, that correlate with the main trait of interest and serve to define the trait or its underlying genetic mechanism more accurately. Endophenotypes may be biochemical, neurophysiologic, cogni-tive, and/or neuropsychologic markers. To fulfill the criteria for a marker trait, an endophenotype should be able to be measured in an objective fashion among clinically unaffected relatives of patients, should occur before the onset of illness, should be stable, and should be associated with an increased risk of clinical illness. This alternative phenotypic strategy may greatly enhance the power of genetic analysis of psychiatric disorders.
Their second concern regarding the potential bias of seasonal variation in 5-HT parameters is irrelevant: it is well-known that 5-HT function might change by less than 20% according to the season (Wirz-Justice 1988), whereas the differences of imipra-mine binding between unaffected relatives and control subjects we report is close to 60% for theKdand 75% for theBmax.
Their third comment is related to the fact that, having shown that unaffected relatives have lower platelet imipramine binding and 5-HT content, we say “this result was consistent with several reports of an association between bipolar disorder and the short allele of the 5-HTTLPR, although this result has not always been replicated.” The association with thesallele reported among bipolar patients in the literature is indeed coherent with reduced 5-HT uptake (Lesch et al 1996). One team (the authors of these criticisms) has reported that depressed children do not differ from control subjects with regard to paroxetine binding, although they carry thel/lgenotype (Nobile et al 1999); however, this is in contradiction with the highly replicated observation of functional expression of the promoter (i.e.,l/landl/s being associated with high uptake and thesallele being associated with reduced uptake; Greenberg et al 1999).
In conclusion, we disagree with the assumption made by Batta-glia and colleagues that it can be misleading to analyze 5-HT functionality in depressed patients and their relatives without 5-HT-TLPR genotyping. Studying these two parameters (protein pheno-type and genopheno-type) separately only reflects the interest of perform-ing two different research strategies independently (i.e., a biochemical versus a genetic association study). We strongly
be-lieve that, in this greatly controversial field, functional studies of proteins, as well as genetic case– control studies, are highly required. But as we said in our article, we are in the process of exploring the genotypes of another larger population of unaffected relatives, first to confirm our preliminary findings and second to explore blindly (without knowing the biochemical endophenotype) the different 5-HTT genotypes (Nakamura et al 2000).
Marion Leboyer
Service de psychiatrie AP-HP
Hoˆpital Henri Mondor et Albert Chenevier 40 Rue De Mesly
Cre´teil, 94000 France
Jean-Marie Launay
Laboratoire central de biochimie AP-HP
Hoˆpital Lariboisie`re Paris, France
PII S0006-3223(00)00914-8
References
Greenberg B, Jolliver T, Huang S-J, Li Q, Bengel D, Murphy D (1999): Genetic variation in the serotonin transporter pro-moter region affects serotonin uptake in human blood plate-lets.Am J Med Genet88:83– 87.
Leboyer M, Belliver F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J (1998): Psychiatry genetics: Search for phenotypes. Trends Neurosci21:102–105.
Leboyer M, Philippe A, Bouvard M, Guilloud-Bataille M, Bondoux D, Tabuteau F, et al (1999a): Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives.Biol Psychiatry45:158 –163.
Leboyer M, Quintin P, Manivet P, Varoqueaux O, Alliaire JF, Launay JM (1999b): Decreased serotonin transporter binding in unaffected relatives of manic depressive patients. Biol Psychiatry46:1703–1706.
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al (1996): Association of anxiety related traits with a polymorphism in the serotonin transporter gene regulatory region.Science274:1527–1531.
Nakamura M, Ueno S, Sano A, Tanabe H (2000): The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants.Mol Psychiatry5:32–38. Nobile M, Begni B, Giorda R, Frigerio A, Marino C, Molteni M,
et al (1999): Effects of serotonin transporter promoter geno-type on platelet serotonin transporter functionality in de-pressed children and adolescents.J Am Acad Child Adolesc Psychiatry38:1396 –1402.
Pierson A, Jouvent R, Quintin P, Perez-Diaz F, Leboyer M (in press): Information processing deficits in relatives of manic-depressive patients.Psychol Med.
Wirz-Justice A (1988): Platelet research in psychiatry. Experi-entia44:147–152.
Correspondence BIOL PSYCHIATRY 335
