Brief ReportsSerotonin transporter gene (HTTLPR) is not in linkage disequilibrium with prepubertal and early adolescent bipolarity
Introduction
Although multiple molecular genetic studies of HTTLPR polymorphisms in adults with BP’s are available Collier et al 1996, Kelsoe et al 1996, Oruc et al 1997, Rees et al 1997, Deoliveira et al 1998, Ewald et al 1998, Furlong et al 1998, Greenberg et al 1998, Gutierrez et al 1998, Hoehe et al 1998, to the best of our knowledge this is the first investigation of a PEA-BP population.
Work on the molecular genetics of PEA-BP was previously impeded by the lack of pediatric–specific research diagnostic instruments and lack of childhood manifestations of DSM-IV mania criteria Geller et al 1995, Geller and Luby 1997. Due to recent databased characterization of prepubertal and early adolescent manifestations of DSM-IV mania criteria Geller et al 1998a, Geller et al 1998b molecular genetic studies of PEA-BP have become feasible. Subjects with PEA-BP in this report had 1) a phenotype that included mania specific criteria (e.g., elated mood,grandiosity), 2) were assessed using PEA–BP specific mania items administered by experienced research clinicians, 3) were directly interviewed about themselves in addition to interviews of parents about their offspring and 4) were ascertained for PEA-BP. By contrast, other investigators (Wozniak et al, 1996) have used 1) criteria of mania that overlap with attention deficit hyperactivity disorder (ADHD) (e.g., irritability, hyperactivity) as the phenotype, 2) have not interviewed the children (only the parents about the children), 3) used non–clinician lay raters, 4) did not use mania items developed for prepubertal children and 5) used a sample ascertained for ADHD. Therefore, it is difficult to compare the Wozniak et al (1996) phenotype to the one used in this report. In this regard, Carlson (1990) proposed a non–databased hypothesis, that manic children would have the episodic course noted for adults. Data, however, from Geller et al (1995 and in press–a) found continuous, non-episodic rapid cycling in PEA-BP cases rather than the episodes with clear onsets and offsets noted for adults with BP. Of note, Papolos et al (1996) also reported rapid cycling in velo-cardio–facial cases with early onset BP.
As noted by others (e.g., Childs and Schriver 1986,) separate study of early onset probands has been an informative approach for phenotypically similar illnesses that have different genetic mechanisms at different ages of onset (e.g., IDDM, Alzheimer’s) and for anticipatory mechanisms (e.g., longer trinucleotide repeats in earlier onset Huntington’s). Evidence for earlier onset of severe illness with greater familial loading has been shown for prepubertal versus adult onset probands with major depressive disorder (Neuman et al 1997). If this model is also found for PEA–BP, high prevalences of rapid cycling and psychosis in the study subjects in this report could be signifiers of severity. Further evidence of severity with early onset BP was provided by Strober et al (1988), who noted relative lithium resistance in adolescents with BP who reported prepubertal onset of psychiatric symptoms. Based on the as yet unresolved issues of continuities versus discontinuities between child and adult onset BP, childhood study is warranted even when studies of serotonergic polymorphisms among populations of adult BP have produced inconsistent results (Greenberg et al 1998). At the HTTLPR locus, of seven case control studies, two were positive Collier et al 1996, Furlong et al 1998 and six were negative Kunugi et al 1997, Oruc et al 1997, Rees et al 1997, Deoliveira et al 1998, Gutierrez et al 1998, Hoehe et al 1998. A transmission disequilibrium (TDT) study of the HTTLPR locus was negative (Greenberg et al 1998) and two linkage and affected sib pair analyses were also negative Kelsoe et al 1996, Ewald et al 1998.
Serotonergic pathways may be especially important for childhood mood disorders based on recent evidence of efficacy of serotonin reuptake inhibitors for depressed children (Emslie et al 1997) compared to previous data on the ineffectiveness of tricyclic antidepressants (Segovia et al in press).
Based on the above, the serotonin transporter linked promoter region (HTTLPR) alleles on chromosome 17 were appropriate candidates for study using a TDT. The HTTLPR short and long alleles (differing by the insertion of a 44 bp segment) have been shown to impact expression of the HTT in lymphoblastoid cell lines (Lesch et al 1996) and in human brain tissue (Little et al 1998). Variation in expression of the HTT would be likely to affect regulation of 5–HT uptake into presynaptic neurons. This uptake mechanism is a site of action of many psychopharmacological agents used to treat mood disorders. Of note, relative lithium resistance in PEA–BP children (Geller et al in press–c), may be related to HTT function.
Section snippets
Methods and materials
The PEA-BP probands were a subset, on whom trio blood collection was complete, from the NIMH funded study “Phenomenology and Course of Pediatric Bipolarity” which comprises 270 subjects. Subjects included 90 with PEA-BP [with or without attention–deficit hyperactivity disorder (ADHD)]; 90 with ADHD (without BP or other major mood disorder) and 90 community controls (without BP, other major mood disorder or ADHD). Subjects in the PEA-BP and ADHD groups were recruited via consecutive case
Results
There were 46 complete trios of PEA–BP probands and both biological parents. The mean age of probands was 11.1 ± 3.0 years and the mean age of onset of PEA–BP was 8.1 ± 4.0 years. The mean CGAS was 43.9 ± 8.9, in the range of severe impairment (0 is worst, 100 is best and less than or equal to 60 is a definite case). Probands manifested elated mood (84.8%), grandiosity (78.3%), rapid cycling (78.3%) and psychosis (63.0%).
Since there were two sets of affected sibling pairs, the total number of
Discussion
Allele distribution was similar to reports from studies of European and American adults.
The negative TDT found in this PEA–BP population is consistent with the one negative TDT (Greenberg et al 1998) and two negative linkage studies Kelsoe et al 1996, Ewald et al 1998 and with most Oruc et al 1997, Rees et al 1997, Deoliveira et al 1998, Gutierrez et al 1998, Hoehe et al 1998, but not all Collier et al 1996, Furlong et al 1998, case control association studies of BP adults. Due to potential
Acknowledgements
Supported by Stanley Foundation (BG, EHC), Nathan Cummings Foundation (BG), and National Institute of Mental Health [R01 MH53063 (BG), K02 MH01389 (EHC)] grants. Zhi Ying Yang and Shuya Yan provided expert technical assistance.
References (39)
- et al.
A functional variant of the serotonin transporter gene in families with bipolar affective disorder
J Affect Dis
(1998) - et al.
Complex and rapid cycling in bipolar children and adolescents
J Affect Disord
(1995) - et al.
Child and adolescent bipolar disorder: A review of the past 10 years
J Am Acad Child Adolesc Psychiatry
(1997) - et al.
Prepubertal and early adolescent bipolarity differentiate from ADHD by manic symptoms, grandiose delusions, ultra–rapid or ultradian cycling
J Affect Disord
(1998) - et al.
Prepubertal and young adolescent bipolarity versus ADHD: Assessment and validity using the WASH–U–KSADS, CBCL, and TRF
J Affect Disord
(1998) - et al.
Serotonin transporter gene and risk for bipolar affective disorder: An association study in a Spanish population
Biol Psychiatry
(1998) - et al.
Age related changes in the association between serotonergic function and aggression in boys with ADHD
Biol Psychiatry
(1997) - et al.
Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation
J Am Acad Child Adolesc Psychiatry
(1998) - et al.
Increased prevalence and earlier onset of mood disorders among relatives of prepubertal versus adult probands
J Am Acad Child Adolesc Psychiatry
(1997) - et al.
A family study of bipolar I disorder in adolescence: Early onset of symptoms linked to increased familial loading and lithium resistance
J Affect Disord
(1988)