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Molecular Psychiatry (2001) 6, 434–439
 2001 Nature Publishing Group All rights reserved 1359-4184/01 $15.00
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ORIGINAL RESEARCH ARTICLE
Role of the serotonin transporter gene in the behavioral
expression of autism

S Tordjman1,2, L Gutknecht1, M Carlier1, E Spitz1, C Antoine2, F Slama1, V Carsalade2, DJ Cohen3,P Ferrari2, PL Roubertoux1 and GM Anderson3 1FRE 2134 CNRS Genetics Neurogenetics and Behavior, 3B Fe´rollerie Street, 45071 Orle´ans cedex 2, France;2Fondation Valle´e, University of Paris-Sud, 7 rue Bense´rade, 94257 Gentilly cedex, France; 3Dept of Child Psychiatry,Yale University School of Medicine, New Haven, CT, USA Keywords: autism severity; extended TDT; HTT promoter
pathophysiology of autism. The important roles of 5- polymorphism; SLC6A4; allelic transmission; modifying loci HT in neurodevelopment9,10 and the rich serotonergic The promoter polymorphism of the serotonin trans-
innervation of limbic areas critically involved in social porter gene (HTT, locus SLC6A4) is of special interest
and affiliative behaviors11 have provided additional, in autism given the well-replicated platelet hypersero-
more theoretical, bases for the 5-HT hypothesis.
tonemia of autism, treatment effects of serotonin reup-
A wide range of 5-HT-related genes can be con- take inhibitors, and the role of serotonin in limbic func-
sidered as possible candidate genes in autism. How- neurodevelopment.
Parent-offspring
ever, the 5-HT transporter gene (HTT, locus SLC6A4), transmission of the long (l) and short (s) alleles of the
encoding both the neuronal and platelet transporter,12 deletion/insertion polymorphism in the HTT promoter
is of particular interest for several reasons. Reports of region was examined in families of 71 children with
a positive correlation between rates of platelet 5-HT autism using the transmission test for linkage disequi-
librium (TDT). Transmission of HTT promoter alleles did

transport and platelet levels of 5-HT13,14 suggest that not differ between probands with autism and their unaf-
the transporter may play a part in the platelet hyperser- fected siblings. However, allelic transmission in pro-
otonemia of autism. The beneficial effects of agents that bands was dependent upon severity of impairments in
block neuronal serotonin transport8 also focus atten- the social and communication domains, with greater s
tion on the possible role of the transporter in the patho- allele transmission in severely impaired individuals and
physiology of autism. Additionally, the reported greater l transmission in mild/moderately impaired indi-
association of a HTT promoter polymorphism with viduals. This relationship between HTT promoter alleles
anxiety in the general population,15 coupled with and severity of autistic impairment was also seen when
reports of higher stress responsivity in autism and an ratings of social and communication behaviors were
increased incidence of anxiety disorder in the families compared across genotypes. The data indicate that HTT
promoter alleles by themselves do not convey risk for

of individuals with autism,16,17 has further stimulated autism, but, rather, modify the severity of autistic
interest in the HTT in autism. Most intriguing have behaviors in the social and communication domains.
been discrepant studies reporting preferential trans- The results require replication and, given the size of the
mission of different alleles of the biallelic promoter groups and subgroups examined, must be considered
region polymorphism in individuals with autism.18,19 preliminary.
The promoter variant consists of a 44 base-pair research on the genetics of autism should carefully
deletion/insertion in a repeat region of the promoter.
assess each of the major behavioral domains and seri-
The deletion or short (s) allele occurs with a frequency ously consider the possible role of modifying loci. Mol-
of approximately 43%, while the long (l) form has an ecular Psychiatry (2001) 6, 434–439.
allele frequency of 57% in samples of predominatelynorthern European ancestry.15,20 It is noteworthy that Autism, a pervasive developmental disorder with pro- the polymorphism is of apparent functional signifi- found deficits in social relatedness, impairments in cance; native lymphoblastoid cell lines with sl or ss language and communication, and symptoms invol- genotypes were reported to have approximately one- ving repetitive behaviors and restricted interests, is half the rates of 5-HT transport, transporter expression, thought to be gene-dependent.1–3 The well-replicated, and HTT mRNA levels as those with the ll genotype.15 but as yet unexplained, platelet hyperserotonemia of After genotyping the HTT promoter alleles in a group autism4,5 has focused attention on the possible role of of 69 French families with autistic children, the trans- the neurotransmitter serotonin (5-hydroxytryptamine, mission of the alleles was examined to determine their 5-HT). Reports of other 5-HT-related abnormalities in influence on risk or susceptibility to autism. A possible autism6,7 and the utility of serotonergic agents in par- modifying role of the HTT on the behavioral pheno- tially ameliorating symptoms in some individuals with typic expression of autism was also studied. This autism8 have also served to increase interest in the possibility was examined by comparing allelic trans- possible involvement of 5-HT in the etiology and mission across severity subgroups formed on the basis Serotonin transporter gene and autism phenotype
S Tordjman et al
of severity of impairment within the major behavioral the total verbal/nonverbal Communication domain was domains of autism, and by comparing domain severity mainly due to two subscores obtained for all patients: failure to initiate or sustain conversational interchange The genotype and allele frequencies observed in the (abbreviated ‘C2V’, as per the ADI-R algorithm) and autistic patients, their parents and siblings are given in lack of varied spontaneous make-believe or social imi- Table 1. The l allele frequency of 56.5% observed in tative play (abbreviated ‘C4’, as per the ADI-R the parents was consistent with frequencies previously algorithm). Values of ⌽2 for C2V and C4 were 0.12 and reported for groups of predominant Western European 0.09 (medium effect size) respectively (Table 2). No sig- ancestry.15,19,20 Genotype distributions in the patient, nificant difference in allelic transmission was observed parental, and sibling groups did not deviate signifi- cantly from Hardy–Weinberg equilibrium.
Preferential transmission of the l allele was observed Considering now the frequencies of l and s alleles in in the autistic patients with a transmission rate of the whole population of autistic individuals, a signifi- 40/64 (62.5%), while the s allele was transmitted at a cantly higher s allele frequency was seen for the Com- rate of 24/64 (37.5%); TDT ␹2 (1) = 4.00, P = 0.046. A bined Social and Communication impairments in the nonsignificant increased transmission of the l allele severely affected subgroup (n = 34; s alleles = 32, l (25/44, 56.8%) was seen in siblings from the same fam- alleles = 36) in comparison with the mildly/moderately ilies. As recommended by Spielman and Ewens,21 a autistic subgroup (n = 30, s alleles = 18, l alleles = 42; TDT directly comparing transmission rates in probands ␹2 (1) = 3.90, P = 0.048). The C2V variable was the only and siblings was performed to account for typing bias subscore giving significant results with respect to allele and preferential transmission arising from non-dis- frequency (severe, n = 38, s alleles = 36, l alleles = 40; order-specific meiotic effects. This more rigorous test mild/moderate, n = 26, s alleles = 14, l alleles = 38; ␹2 of disease linkage did not reveal a significant difference between patients and siblings (TDT ␹2 (1) = 0.35,P = 0.55).
The s allele was transmitted at significantly higher observed in groups of patients with different HTT pro- rates in the severely autistic subgroup in comparison moter genotypes showed that individuals bearing the with the mildly/moderately autistic subgroup for the S (ss and ls) genotype had significantly more severe total Social Interaction, the total verbal/nonverbal impairments than L (ll) genotype individuals for the Communication, and the Combined Social and Com- Combined Social and Communication domain and for munication impairments (Table 2). Conversely, the l the C2V subscore (Wilcoxon Rank Sum test, Z = 1.95, allele was transmitted at lower rates in the more severe P = 0.050 and Z = 2.12, P = 0.033, respectively). The s subgroup in comparison with the mild/moderate sub- allele was also associated with the more severe impair- group. Similar results were obtained for the nonverbal ments in the social and communication domains when communication domain (TDT ␹2 (1) = 3.92, P = 0.048).
comparisons were performed across all three geno- The strength of the significant association between the types: rank ordered Kruskal–Wallis test average scores transmitted allelic forms and the total behavioral for Combined Social and Communication impairments scores determined by the Cramers’ statistic ⌽2 ranged were 2.25, 2.6, 2.80 in the ll (n = 24), ls (n = 30), ss from 0.08 to 0.18, values which are considered by Cohen22 to be of medium effect size. The difference in P = 0.076); K–W test average scores for C2V were 2.15, Serotonin transporter promoter polymorphism: distribution of genotypes and alleles in individuals with autism and Number of participants with genotype (%) aIncludes only the informative trios (ie, with at least one heterozygous parent).
Serotonin transporter gene and autism phenotype
Transmission of 5-HTTLPR alleles in autism according to behavioral domain and severity of impairment Behavioral domain/severity of autistic impairment aTDT ␹2 (1) = 3.89, P = 0.049.
bTDT ␹2 (1) = 4.52, P = 0.033. The difference was mainly due to two subscores: failure to initiate or sustain conversationalinterchange (mild/moderate, n = 16, l alleles = 19, s alleles = 4; severe, n = 26, l alleles = 17, s alleles = 19; TDT ␹2 (1) = 7.63,P = 0.006), and lack of varied spontaneous make-believe or social imitative play (mild/moderate, n = 20, l alleles = 22, salleles = 7; severe, n = 22, l alleles = 14, s alleles = 16; TDT ␹2 (1) = 5.28, P = 0.022).
cTDT ␹2 (1) = 7.39, P = 0.007.
*Number of autistic individuals in subgroup.
2.6, 2.88 in the ll (n = 24), ls (n = 30), ss (n = 10) geno- tional polymorphisms have not been found in the types, respectively (␹2 (2) = 7.23, P = 0.030).
Although the l allele of the biallelic HTT promoter Thus, although, it is difficult to definitively rule out polymorphism was transmitted at above chance rate in any of these possibilities, it does appear that the most individuals with autism, the allele preference was parsimonious explanation for all the data reported to slight and the level of significance was low (P = 0.046); date is that the 5-HTTLPR is not associated with risk the low a priori probability of linkage requires high lev- to autism. It should be noted that unaffected-sibling els of statistical significance to avoid false positive control groups were not used in the prior studies; as findings.23 In addition, l allele transmission was not mentioned, this raises the possibility that a general bias significantly elevated when compared with the rate of transmission may have influenced the previous observed in unaffected siblings. The use of a sibling results. The absence of replicated disorder-specific control group is recommended for rigorously estab- preferential transmission is consistent with the results lishing preferential transmission, as the approach of the Autism Consortium sib-pair study, where no accounts for any general bias of transmission. In the increased sharing in the vicinity of the HTT locus on absence of a significant difference in transmission 17q12 was observed,25 and with the results of a recent between probands and unaffected siblings, one can not conclude that there is a linkage with risk.
In contrast, the data regarding possible behavioral Previously reported studies of HTT promoter allele associations (allelic transmission and allelic fre- transmission in autism have found preferential s allele quencies in the severity subgroups, as well as compari- transmission in an American group,18 increased l allele son of autism severity performed across genotypes) transmission in a German sample,19 and similar s and l consistently point to the s allele being associated with allele transmission in a combined European/American the more severe impairments in the communication group.24 There are several possible explanations for the and social interaction domains. Conversely, the l allele discrepant results. They could be due to differences in may be exerting a protective effect, mitigating deleteri- behavioral characteristics of the European and Amer- ous effects of other risk-associated or modifying genes.
ican patients, and the allelic effects on behavior may Given the size of the groups and subgroups examined, differ substantially across populations with different these findings must be considered still preliminary.
genetic backgrounds; the potential importance of However, if replicated, our findings would indicate behavioral differences across groups is underlined by that the HTT promoter polymorphism by itself does the behavioral associations described in the Results not convey risk for autism, but instead influences the section. However, the American and European samples behavioral phenotypic expression of autism. Interest- were all diagnosed using identical instruments, and it ingly, there are a number of recent observations of actually appears that the German and American monoamine-related genes having modifying effects on cohorts are more similar with respect to average IQ the behavioral phenotypic expression of neuropsychi- than the German and French (present) groups. Alterna- atric disorders in the absence of apparent associations tively, the observed associations could be a reflection with risk. Of special relevance are reports that 5- of linkage to another etiologically significant site HTTLPR alleles influence the severity of alcohol with- within the HTT gene or another gene within the HTT drawal,27 the severity of hallucinations and thought region. However, it can be argued here that other func- disorder in schizophrenia;28 and the degree of season- Serotonin transporter gene and autism phenotype
S Tordjman et al
ality in seasonal affective disorder.29 The observation based on 9 items), and Total Stereotypies (8 items). A that infants homozygous for the s allele have lower median score for a Combined Social/Communication orientation and alertness scores30 may also be parti- domain (on 28 items) was also obtained; a similar com- cularly relevant to our finding in autism.
bined social and communication domain score is for- It is suggested that future research on the genetics of med as part of the algorithm used with the PL-ADOS autism should carefully assess each of the major observational scale of Dilavore, Lord and Rutter.35 The behavioral domains and should seriously consider the median domain score of autistic impairments for each possible role of modifying loci. Finally, our data under- individual was then used to dichotomize subjects line the importance of using a methodology in which according to autism severity in each of the domains: genetic transmission is studied in concert with a individuals were grouped into mild–moderate (median detailed examination of behavioral phenotype.
1–2) and severe (median 3) impairment. Interjudgereliability with respect to the critical distinction Materials and methods
between mild/moderate and severe impairment wasexcellent, with an interjudge agreement of 95% Patients and behavioral assessments observed between two expert raters (given the large Children with autism (n = 71, 46 males and 25 females, number of severely autistic patients in our sample, it average age in years ± SD: 11.6 ± 4.5 with a range of was possible to clearly distinguish the severely autis- 4.6–19.5), all Caucasian, were recruited from French child psychiatry day hospitals. All subjects were physi-cally healthy and had no history of encephalopathy orneuro-endocrinological disease. Parents, all func- tioning members of society, and siblings of the autistic DNA of autistic probands was extracted from EDTA- probands also participated. All ‘unaffected siblings’ anticoagulated whole blood; DNA of siblings and par- were attending regular schools, none met diagnostic ents was obtained from buccal cavity epithelial cells.36 criteria for autism or other pervasive developmental The HTT promoter polymorphic region was amplified disorders. The protocol was approved by the ethics committee of Biceˆtre Hospital. Written informed con- TAATGT3Ј (position: −1400 to −1377) and 5ЈGGA sent was obtained from parents and from children able CCGCAAGGTGGGCGGGA3Ј (position: −1001 to −982) to understand the study and consent procedure. Cogni- as specified by Gelernter and colleagues.20 These pri- tive functioning of autistic probands was assessed by mers gave after PCR amplification two products, a short two psychologists using the age-appropriate Wechsler variant (s) of 375 bp and a long variant (l) of 419 bp.
intelligence scales (WPPSI-R; WISC-R; WAIS-R) and Amplification conditions were modified from those of the Kaufman K-ABC.31 All autistic probands were cog- Gelernter and colleagues. PCR was performed in a final nitively impaired (mean full scale IQ ± SD: 42.2 ± 3.2, volume of 15 ␮l containing 37.5 ng genomic DNA, 0.75 with a range of 40–58; mean verbal IQ ± SD: 45.5 ± 2.2, units of Klen Taq polymerase from AbPeptides (St with a range of 45–57; mean performance IQ ± SD: Louis, MO, USA) with the manufacturer’s PC2 buffer 45.6 ± 4.1, with a range of 45–80). Behavioral assess-ments were performed using the Autism Diagnostic Interview–Revised32 for 64 individuals with autism.
ammonium sulfate, 3.5 mM MgCl2, and 150 ␮g ml−1 The ADI-R, an extensive, semi-structured parental BSA), 0.5 ␮M of each primer, base concentration interview, was conducted by two trained psychiatrists.
0.28 mM and 5 ␮l cresol red. Samples were amplified The ADI-R scale assessed the three major domains of with initial denaturation at 95°C for 4 min, followed by autistic impairments: reciprocal social interactions, 40 cycles at 96/58/72°C for 30, 40, and 60 s, respect- verbal and non-verbal communication, stereotyped ively. The PCR was ended by a final extension at 72°C behaviors and restricted interests. Based on direct for 8 min. PCR products were separated on 2% agarose clinical observation of the child by two independent electrophoresis gel and visualized with ethidium bro- child psychiatrists, a diagnosis of autism was made according to the criteria of DSM-IV,33 ICD-10 and Of the 69 families recruited, 62 complete trios CFTMEA34 and was confirmed by the ADI-R ratings.
(mother, father, affected offspring) were genotyped, The severity of impairments in the major domains with 46 of the trios being informative (ie, with at least of autism were scored using the subset of ADI-R items one heterozygous parent). These 46 autistic probands included in the ADI-R algorithm. Taking into account (29 males and 17 females, average age in years ± SD: that the ADI-R items are scored on an ordinal scale 11.4 ± 5.2 with a range of 5–19.2) were all cognitively (from 1 to 3 according to autism severity; the ‘0’ coding impaired (mean full scale IQ ± SD : 40.2 ± 1.2, with a means that the autistic behavior was not present), we range of 40–48; mean verbal IQ ± SD: 45.6 ± 2.3, with a took the median value of all items belonging to the range of 45–57; mean performance IQ ± SD: 45.1 ± 0.5, same domain of autistic impairment according to the with a range of 45–48) and 25 probands were nonverbal ADI-R algorithm. This gave a score of central tendency according to the ADI-R criteria. Two of the informative for each of the three domains: Total Social Interaction trios consisted of parents and an affected sibling. In the (15 items), Total Verbal/nonverbal Communication (13 informative families, 32 unaffected siblings (20 single items; for non verbal patients the median score was sibs and six pairs of sibs) were also genotyped.
Serotonin transporter gene and autism phenotype
2 Smalley SL, Asarnow RF, Spence MA. Autism and genetics. A dec- The transmission test for linkage disequilibrium ade of research. Arch Gen Psychiatry 1988; 45: 953–961.
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5 McBride PA, Anderson GM, Hertzig ME, Snow ME, Thompson SM, the ADI-R-derived autism severity subgroups was ana- Khait VD et al. Effects of diagnosis, race, and puberty on platelet lyzed using the TDT. A similar methodology was serotonin levels in autism and mental retradation. J Am Acad Child employed by Spielman and colleagues37 (and personal Adolesc Psychiatry 1998; 37: 767–776.
communication, 1998) when examining transmission 6 McBride PA, Anderson GM, Hertzig ME, Sweeney JA, Kream J, Cohen DJ et al. Serotonergic responsivity in male young adults in subgroups. The extension of the TDT to examining with autistic disorder. Results of a pilot study. Arch Gen Psychiatry the relationship between continuous or categorical 1989; 46: 213–221.
variables, including severity, has been discussed in 7 Novotny S, Hollander E, Allen A, Mosovich S, Aronowitz B, Cart- detail by Waldman and colleagues.38–40 Although most wright C et al. Increased growth hormone response to sumatriptan previous studies of genetic influences on severity have challenge in adult autistic disorders. Psychiatry Res 2000; 94:
173–177.
used a case-control (allele frequency) approach, the 8 McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, power, suitability and utility of the ‘extended-TDT’ for Price LH. A double-blind, placebo-controlled study of fluvoxamine examining transmission in subgroups is clear. The in adults with autistic disorder. Arch Gen Psychiatry 1996; 53:
allelic frequencies in the severity subgroups were com- 9 Moiseiwitsch JR, Lauder JM. Serotonin regulates mouse cranial pared using ␹2 tests. In order to balance Type I and neural crest migration. Proc Natl Acad Sci USA 1995; 92: 7182–
Type II errors in the statistical analysis of behavioral domains, a hierarchical strategy was used.41 First, the 10 Whitaker-Azmitia PM, Azmitia EC. Astroglial 5-HT1a receptors and total behavioral domains were examined. If there was S-100 beta in development and plasticity. Perspect Dev Neurobiol a significant result for an overall domain, then a further 1994; 12: 233–238.
11 Bachevalier J. Medial temporal lobe structures and autism. A level of analysis occurred on the subscores included in review of clinical and experimental findings. Neuropsychologia the domain. The strength of the significant associations 1994; 32: 627–648.
12 Lesch KP, Wolozin BL, Murphy DL, Riederer P. Primary structure behavioral scores was determined by the Cramers’ stat- of the human platelet serotonin (5-HT) uptake site: identity with the brain 5-HT transporter. J Neurochem 1993; 60: 2319–2322.
13 Cook EH, Arora RC, Anderson GM, Berry-Kravis EM, Yan SY, Yeoh In a parallel approach to the issue of clinical associ- HC et al. Platelet serotonin studies in hyperserotonemic relatives ations, autistic behavioral ratings observed in groups of of children with autistic disorder. Life Sci 1993; 52: 2005–2015.
patients with different HTT promoter genotypes were compared. Comparisons were performed across all (Cercopithecus aethiops sabaeus) whole blood serotonin level is three genotypes using the Kruskal–Wallis test and after determined by platelet uptake sites. Life Sci 1987; 41: 1539–1546.
15 Lesch KP, Bebgel D, Heils A, Sabol SZ, Greenberg BD, Petri S et combining the ls and ss genotypes (S genotype, ss and al. Association of anxiety-related traits with a polymorphism in ls, genotype, ll) using the Wilcoxon Rank Sum test. The the serotonin transporter gene regulatory region. Science 1996; 274:
s allele genotypes were collapsed given the suggested dominant s allele effects on serotonin transport15 and 16 Piven P, Chase GA, Landa R, Wzorek M, Gayle J, Cloud D et al.
Psychiatric disorders in parents of autistic individuals. J Am Acad to preserve power in examining s allele effects.
Child Adolesc Psychiatry 1991; 30: 471–478.
17 Tordjman S, Anderson GM, McBride PA, Hetzig M, Snow M, Hall Acknowledgements
L et al. Plasma beta-endorphin, adrenocorticotropin hormone, and We thank Richard Spielman for his helpful comments.
cortisol in autism. J Child Psychol Psychiatry 1997; 38: 705–715.
18 Cook EH, Courchesne R, Lord C, Cox NJ, Yan S, Lincoln A et al.
This work was supported in France by the Institut Evidence of linkage between the serotonin transporter and autistic National de la Sante´ et de la Recherche Me´dicale disorder. Mol Psychiatry 1997; 2: 247–250.
(contrat Equipe de Recherche Clinique Associe´e a` I’In- 19 Klauck SM, Poustka F, Benner A, Lesch K, Poutska A. Serotonin stitut National de la Sante´ et de la Recherche transporter (5-HTT) gene variants associated with autism? Hum
Mol Genet
1997; 6: 2233–2238.
Me´dicale), the Centre National de la Recherche Scienti- 20 Gelernter J, Kranzler H, Cubells JF. Serotonin transporter protein fique (Formation de Recherche en Evolution 2134), the (SLC6A4) allele and haplotype frequencies and linkage disequilib- Ministe`re de I’Education Nationale, de la Recherche et ria in African and European American and Japanese populations de la Technologie, the Conseil de la Re´gion Centre.
and in alcohol dependent subjects. Hum Genet 1997; 101: 243–246.
Support in the USA was provided by the National 21 Spielman RS, Ewens WJ. The TDT and other family-based tests for linkage disequiliibrium and association. Am J Hum Genet 1996; 59:
Institute of Mental Health (MH30929) and the National Institute of Child Health and Human Development 22 Cohen J. Statistical Power Analysis for the Behavioral Sciences (HD03008), and the Korczak Foundation for Autism (2nd edn). Academic Press: New York, 1977.
23 Kendler KS, MacLean CJ, O’Neill FA, Burke J, Murphy B, Duke F et al. Evidence for a schizophrenia vulnerability locus on chromo-some 8p in the Irish study of high-density schizophrenia families.
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