International Meeting for Autism Research: Genome Scan of Serotonin Levels In Utah Families with Autism Spectrum Disorders

Genome Scan of Serotonin Levels In Utah Families with Autism Spectrum Disorders

Thursday, May 12, 2011
Elizabeth Ballroom E-F and Lirenta Foyer Level 2 (Manchester Grand Hyatt)
2:00 PM
D. Bilder1, H. Coon2, E. H. Cook3, D. Cannon2, M. Hobbs4, D. Wilkins5, R. J. Robison6 and W. M. McMahon7, (1)Utah Autism Research Project, University of Utah, Salt Lake City, UT, (2)Utah Autism Research Project, University of Utah , Salt Lake City, UT, (3)University of Illinois at Chicago, Chicago, IL, (4)Division of Infectious Disease, University of Utah, Salt Lake City, UT, (5)Center for Human Toxicology, Salt Lake City, UT, (6)Psychiatry Research Clinic, University of Utah School of Medicine, Salt Lake City, UT, (7)Department of Psychiatry, University of Utah, Salt Lake City, UT
Background: Autism Spectrum Disorders (ASDs) are highly heritable conditions.  Elevated whole blood serotonin levels have long been associated with ASDs, with several candidate genes proposed to explain this relationship. 

Objectives: The purpose of this study is (1) to perform a genome scan to determine chromosome locations with variants possibly explaining variation in blood serotonin levels among individuals with ASDs and their families, (2) to cross-reference suggestive and significant chromosomal locations from this scan with locations of known serotonin-related genes which may merit closer exploration, and (3) explore gender effects and associations with other phenotypes measured in these families. 

Methods:  Serotonin levels, platelet count, and DNA were available on a total of 432 individuals from 69 multiplex and extended Utah families.  119 of these subjects had ASDs, and 316 were unaffected family members.  Serotonin was measured using a sensitive and specific liquid chromatography-tandem mass spectrometric method (LC-MS/MS).  The precision and accuracy of the method were determined from replicate analyses of quality control (QC) samples fortified at low and high QC concentrations.  Individuals taking medications known to alter serotonin were excluded from the analysis.  Serotonin levels were adjusted for the effects of age, sex, and platelet count.  Genotypes from the 6k single nucleotide polymorphism (SNP) Illumina Linkage Panel 12 were provided by the Center for Inherited Disease Research (CIDR).  SNPs were screened for errors, low informativeness (minor allele frequency < 0.10), and high linkage disequilibrium, leaving 4718 SNPs for analysis.  Linkage analyses not assuming a genetic model (nonparametric) were performed using quantitative serotonin levels with the SOLAR analysis package. 

Results:  Individuals with ASD were significantly more likely than unaffected family members to have an adjusted serotonin level 1 standard deviation above the mean (p=0.004).  Serotonin demonstrated significant heritability (h2=0.75) in these families.  Using data from all subjects, the highest lod score was 2.56 on chromosome 8 at 115 centiMorgans.  When analyses were restricted to males only, this result increased to a lod score of 3.04.  Positive results with scores over 2 were also found for males only on chromosomes 2, 11, and 12.  Females only showed positive results over 2 on chromosomes 2 and 9.  Initial database searches have not indicated any apparent relationship between these regions and known serotonin-related genes. 

Conclusions:  Analyses indicate multiple chromosomal locations that may contain DNA variants influencing serotonin levels in families with ASDs.  In addition, our results suggest possible gender-specific DNA variants.  We are refining our analyses, and investigating possibilities that variants in these regions could be associated with genes involved in regulation and/or expression of serotonin.

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