Abnormalities in serotonin metabolism are one of the few consistent biological findings observed in autistic individuals. Although genome wide linkage scans and candidate gene studies have implicated various loci in the serotonin pathway, the results have been inconsistent. Our study was designed to test two underlying hypotheses. First, does any prominent candidate gene in the serotonin system display a major locus effect in a previously unexamined dataset? Our data suggests that a single locus effect resides within HTR3A, which provided strong association results with a p-value of 0.0002 (p=0.022 corrected) at rs1150220. This result was not restricted to the male subset. This particular SNP is intronic, and there is no current data to suggest a functional consequence of this variation.
Second, do the serotonin system genes provide interesting multilocus interaction effects? This question is driven, in part, by the possibility of genetic buffering, where the moderate dysfunction of one or more genes (perhaps due to common variation) is compensated by other genes. Should more than one gene have moderately altered function, the entire system may then be perturbed. Our MDR analysis identified a moderate interactive effect between rs10830962 and rs1007631 (p-value of 0.01) in a two-way interaction model in the overall dataset. Neither of these SNPs resides within the coding sequence of a gene, with rs10830962 near MTNR1B and rs1007631 near SLC7A5. There is no obvious biological explanation for this interaction, since the genes are not adjacent in the pathway and there is no evidence of direct biological interaction. However, it is possible that these SNPs, or others in LD with them, may have as yet unknown regulatory functions.
is an interesting candidate gene. The product of HTR3A
belongs to the ligand-gated ion channel receptor superfamily, it is permeable to Na+, K+ and C2+ ions. HTR3A
is composed of four hydrophobic transmembrane segments, a large extracellular domain containing a Cys-Cys loop, a long intracellular segment between the third and the fourth transmembrane regions and an extracellular C-terminus (47
is located on chromosome 11q23.1–23.2 and encodes subunit A of the type 3 receptor for serotonin, and functions as a neurotransmitter, a hormone, and a mitogen. This receptor causes fast, depolarizing responses in neurons after activation. It functions to mediate rapid synaptic transmission in the brain (48
). At the presynaptic location of the receptor it mediates neurotransmitter release (49
). The gene consists of nine exons and spans approximately 15 kb (50
contains 9 known coding variations (3 non-synonymous). HTR3A
is highly expressed in the central nervous system as well as in the colon, intestine and stomach (51
). For HTR3A
to have the highest activity it forms heteromeric combinations with HTR3B
. However, HTR3A
is unusual in that it can form homomeric assemblies with reduced channel activity (52
). Alternatively spliced transcript variants encoding different isoforms have also been identified.
The serotonin system has been widely investigated in neuropsychiatric disorders and has been implicated as having a role in learning, mood, thermoregulation, sleep, sexuality, and appetite (53
). Variations in HTR3A
has specifically been linked to several mental disorders such as bipolar disorder (57
), harm avoidance in women (59
) and schizophrenia (60
). Furthermore, HTR3B
was associated to depression in a sample of Japanese women with major depression (61
). Krzywkowski et al. demonstrated that naturally occurring variation in the receptor created a drastic change in their function and expression (62
). Thus, dysfunction of HTR3A
resulting in altered neurotransmission within the pathway is a possible source of insight in elucidating the etiology of the disorder.
Even though we captured a significant number of the common variation for these genes, our study is not fully comprehensive. There could be variation in regulatory elements for these genes outside of the coding regions, within the intronic regions not completely covered by our analysis, and even outside the flanking regions selected in our study. There could be an extreme level of locus heterogeneity, which has a significant negative impact on power both for PDT and MDR analyses. Since we only examined common variation, the underlying effects could arise from multiple rare variants in one or more of these genes.