Investigation of potential gene-gene interactions between APOE and RELN contributing to autism risk.
BACKGROUND
Several candidate gene studies support RELN as susceptibility gene for autism. Given the complex inheritance pattern of autism, it is expected that gene-gene interactions will exist. A logical starting point for examining potential gene-gene interactions is to evaluate the joint effects of genes involved in a common biological pathway. RELN shares a common biological pathway with APOE, and Persico et al. have observed transmission distortion of the APOE-2 allele in autism families.


OBJECTIVE
We evaluated RELN and APOE for joint effects in autism susceptibility.


METHODS
A total of 470 Caucasian autism families were analyzed (265 multiplex; 168 trios with no family history; 37 positive family history but only one sampled affected). These families were genotyped for 11 RELN polymorphisms, including the 5' untranslated region repeat previously associated with autism, as well as for the APOE functional allele. We evaluated single locus allelic and genotypic association with the pedigree disequilibrium test and geno-PDT, respectively. Multilocus effects were evaluated using the extended version of the multifactorial dimensionality reduction method.


RESULTS
For the single locus analyses, there was no evidence for an effect of APOE in our data set. Evidence for association with RELN (rs2,073,559; trio subset P=0.07 PDT; P=0.001 geno-PDT; overall geno-PDT P=0.05), however, was found. For multilocus geno-PDT analysis, the joint genotype of APOE and RELN rs2,073,559 was highly significant (trio subset, global P=0.0001), probably driven by the RELN single locus effect. Using the extended version of the multifactorial dimensionality reduction method to detect multilocus effects, there were no statistically significant associations for any of the n-locus combinations involving RELN or APOE in the overall or multiplex subset. In the trio subset, 1-locus and 2-locus models selected only markers in RELN as best models for predicting autism case status.


CONCLUSIONS
Thus, we conclude that there is no main effect of APOE in our autism data set, nor is there any evidence for a joint effect of APOE with RELN. RELN, however, remains a good candidate for autism susceptibility.
Ashley-Koch
Allison E
AE
Center for Human Genetics, Department of Medicine, Duke University Medical Center, Snyderman Genomic Sciences Building, Durham, NC 27710, USA. allison.ashleykoch@duke.edu
Jaworski
James
J
Ma
De Qiong
DQ
Mei
Hao
H
Ritchie
Marylyn D
MD
Skaar
David A
DA
Robert Delong
G
G
Worley
Gordon
G
Abramson
Ruth K
RK
Wright
Harry H
HH
Cuccaro
Michael L
ML
Gilbert
John R
JR
Martin
Eden R
ER
Pericak-Vance
Margaret A
MA
D001057:Apolipoproteins E / Q000235:genetics*; D001321:Autistic Disorder / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D004578:Electron Spin Resonance Spectroscopy; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D000091042:Reelin Protein; D018570:Risk Assessment; D012697:Serine Endopeptidases / Q000235:genetics*; D014481:United States; D044465:White People
D001057:Apolipoproteins E; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717127:RELN protein, human; D012697:Serine Endopeptidases