Self-injury in autism spectrum disorder: An effect of serotonin transporter gene promoter variants
Introduction
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with significant phenotypic variability characterized by social and communication deficits in addition to restricted and repetitive behaviors. While environmental risk factors play a role, the etiology of ASD is primarily due to complex genetics; both common genetic polymorphisms and rare causal variants are now understood to play causative roles. Genetic heterogeneity contributes to the challenges in identifying susceptibility genes, so previous studies have attempted to identify subgroups of patients with homogeneous phenotypes. Focusing genetic analyses on such phenotypic differences may facilitate identification of the genetic factors underlying the variability within the disorder.
Most investigators have found that serotonin levels measured in whole blood are significantly higher on average in subjects with ASD than normal controls, and approximately one-third of autistic individuals have hyperserotonemia (Schain and Freedman, 1961, Gabriele et al., 2014). Whole blood serotonin levels in these studies were measured from the platelet content of serotonin since greater than 99 percent of whole blood serotonin is found in the platelet fraction (Anderson et al., 1987). In previous work, our group examined the relationship between whole blood serotonin and repetitive behaviors in ASD in order to clarify whether levels of this neurochemical were associated with specific behavioral symptoms of autism. An inverse relationship was found between whole blood serotonin level and aggression to self (Kolevzon et al., 2010) using the Autism Diagnostic Interview-Revised (ADI-R; Lord et al., 1994). Of interest, much literature to date supports the presence of an inverse relationship between serotonin or its metabolite (5HIAA) and aggression (Moore et al., 2002, Siever, 2008, Seo et al., 2008, Lesch and Merschdorf, 2000). The relationship between serotonin and aggressive or violent behavior is evident in aggression to either self or others, and studies have implicated the role of serotonin transporter gene (5HTT) polymorphisms to self-directed aggression, such as suicidal behavior.
Over 20 polymorphisms of 5HTT have been identified, some of particular interest because of their functional effects on gene expression and serotonin transporter functioning. One such polymorphism is a 44 base-pair insertion/deletion in the 5′-flanking regulatory region of the serotonin transporter gene promoter region (5HTTLPR) (Goveas et al., 2004), corresponding to two common allelic variants—long (L) allele and short (S) allele respectively. The short variant has lower mRNA transcriptional efficiency, leading to lower gene expression and subsequent lower serotonin reuptake activity (Goveas et al., 2004, Lesch et al., 1996). An association between self-directed injury, such as suicidal behavior, and 5-HTTLPR allele frequency has been demonstrated but with conflicting results. Some studies find higher frequency of the L allele in depressed suicide victims compared to non-suicidal controls (Du et al., 1999, Russ et al., 2000), while others show an association between the S allele and lethality of suicidal behavior (Bondy et al., 2000, Bellivier et al., 2000, Courtet et al., 2001). In addition, Hankin et al. (2011) found that youth carrying one or two copies of the S allele of 5-HTTLPR exhibited more traits of Borderline Personality Disorder, a condition that is often associated with non-suicidal self-injury. These data suggest self-injurious behavior as a possible phenotype associated with serotonin regulation.
The role of 5-HTT gene polymorphisms in ASD has been extensively explored, but with inconsistent results. Attempts to determine whether there is a transmission bias of either L or S allelic variants of 5HTTLPR in autism have yielded conflicting results, including over-transmission of S (Devlin et al., 2005; Sutcliffe et al., 2005) over-transmission of L (Klauck et al., 1997, Yirmiya et al., 2001), or no significant association of either allele (Huang and Santangelo, 2008). Studies of association between allelic frequency and phenotypic subgroups have likewise yielded disparate results. Over-transmission of the S allele has been demonstrated in patients with ASD compared with their unaffected siblings, and especially patients with severe social or communication deficits (Tordjman et al., 2001). Brune et al. (2006) also found that patients with SL or SS genotypes had more severe impairments in social and communication domains but patients with the LL genotype had more severe stereotyped, repetitive behavior, and aggression. However, Ramoz et al. (2006) found no association between variants at the 5HTTLPR locus in ASD or more specifically in relatively rigid-compulsive and obsessive–compulsive patients, a finding supported by McCauley et al. (2004). However, interpreting results from these studies may be confounded by the possibility of ethnicity effects; a meta-analysis by Huang and Santangelo (2008) found that in family based studies of ASD, United States samples with various ethnicities had preferential transmission of the S allele while European and Asian samples had no allelic association (Huang and Santangelo, 2008).
Adding further to this complexity, 5-HTTLPR has recently been shown to be more complex—with L subdivided into La and Lg variants and S into Sa and Sg variants. The Lg variant results from a single-base substitution (A>G) and has a binding site for a transcription factor that suppresses 5-HTT transcription (Hu et al., 2005, Hu et al., 2006, Kraft et al., 2005). The Lg variant therefore functions similar to the S variant and thus can be grouped with it. To extend our previous findings that found an inverse relationship between whole blood serotonin and self-injury as assessed by the ADI-R, this study examined the association between self-injurious behavior and allelic frequencies of La vs. S/Lg polymorphisms of 5HTTLPR. It was hypothesized that self-injury in children with ASD would be associated with an increased frequency of S or Lg (vs. La) alleles because S and Lg alleles are associated with decreased uptake of serotonin into platelets where serotonin is mainly stored.
Section snippets
Materials and methods
Subjects were part of an ongoing recruitment for multiplex families at the Seaver Autism Center for Research and Treatment. Affected families were required to have at least one case of autism and another case with autism or a sub-threshold autism-related disorder based on Diagnostic and Statistical Manual Fourth Edition (DSM-IV) criteria. Individuals known to have medical conditions associated with autism (e.g. tuberous sclerosis, fragile X syndrome, phenylketonuria) were excluded. Cases with
Results
The 64 subjects came from 44 families. The range of ages was from 2 to 16 years-old (mean 6.85, S.D.+2.75). Forty-five cases were male (70.3%). Whole blood serotonin levels ranged from 78 to 471 ng/ml and approximately one-third of subjects had levels greater than 252 ng/ml (skewness=0.902, SE=0.299). The ethnic composition of the sample was 78.1% white, 14.0% “other” and 7.9% was classified as unknown or ethnicity data was missing. For the S/La/Lg alleles of the 5HTTLPR gene, the frequency of
Discussion
This study showed a significant difference in the frequency of 5HTTLPR alleles between children with autism with and without self-injurious behaviors. Children with self-injury were more likely to have La alleles whereas children without self-injury were more likely to have Lg alleles, a finding that contradicts our initial hypothesis. The hypothesized association between allele frequency and self-injury was based on the finding that whole blood serotonin levels were inversely related to
Acknowledgments
This work was supported in part by the AACAP/Eli Lily Young Investigator Award (Dr. Kolevzon), the Beatrice and Samuel A. Seaver Foundation (Drs. Kolevzon and Silverman), Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center (Dr. Kolevzon), the Jean Young and Walden W. Shaw Foundation (Dr. Cook), and The Daniel X. & Mary Freedman Foundation for Academic Psychiatry (Dr. Cook).
References (38)
- et al.
Determination of serotonin in whole blood, platelet-rich plasma, platelet-poor plasma and plasma ultrafiltrate
Life Science
(1987) - et al.
Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders
Biological Psychiatry
(2000) - et al.
Platelet serotonin studies in familial hyperserotonemia of autism
Life Sciences
(1993) - et al.
Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims
Biological Psychiatry
(1999) - et al.
Blood serotonin levels in autism spectrum disorder: a systematic review and meta-analysis
European Neuropsychopharmacology
(2014) - et al.
Platelet serotonin content correlates inversely with life history of aggression in personality-disordered subjects
Psychiatry Research
(2004) - et al.
Serotonin transporter promoter gain-of-function genotypes are linked to obsessive–compulsive disorder
The American Journal of Human Genetics
(2006) - et al.
The relationship between repetitive behaviors and whole blood serotonin in autism
Psychiatry Research
(2010) - et al.
Sequence analysis of the serotonin transporter and associations with antidepressant response
Biological Psychiatry
(2005) - et al.
Lack of evidence for association of the serotonin transporter gene SLC6A4 with autism
Biological Psychiatry
(2006)
Analysis of catechol-O-methyltransferase and 5-hydroxytryptamine transporter polymorphisms in patients at risk for suicide
Psychiatry Research
Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children
Journal of Pediatrics
Role of serotonin and dopamine system interactions in the neurobiology of impulsive aggression and its co morbidity with other clinical disorders
Aggression and Violent Behavior
Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid–compulsive behaviors
The American Journal of Human Genetics
The serotonin transporter gene in aggressive children with and without ADHD and nonaggressive matched controls
Annals of the New York Academy of Sciences
Possible association of the short allele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) with violent suicide
Molecular Psychiatry
5-HTTLPR genotype-specific phenotype in children with adolescents with autism
The American Journal of Psychiatry
Association between violent suicidal behavior and the low activity allele of the serotonin transporter gene
Molecular Psychiatry
Association of the serotonin transported and 5HT1Dβ receptor genes with extreme, persisten, and pervasive aggressive behavior in children
Psychiatric Genetics
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