Examination of NRCAM, LRRN3, KIAA0716, and LAMB1 as autism candidate genes.
BACKGROUND
A substantial body of research supports a genetic involvement in autism. Furthermore, results from various genomic screens implicate a region on chromosome 7q31 as harboring an autism susceptibility variant. We previously narrowed this 34 cM region to a 3 cM critical region (located between D7S496 and D7S2418) using the Collaborative Linkage Study of Autism (CLSA) chromosome 7 linked families. This interval encompasses about 4.5 Mb of genomic DNA and encodes over fifty known and predicted genes. Four candidate genes (NRCAM, LRRN3, KIAA0716, and LAMB1) in this region were chosen for examination based on their proximity to the marker most consistently cosegregating with autism in these families (D7S1817), their tissue expression patterns, and likely biological relevance to autism.


METHODS
Thirty-six intronic and exonic single nucleotide polymorphisms (SNPs) and one microsatellite marker within and around these four candidate genes were genotyped in 30 chromosome 7q31 linked families. Multiple SNPs were used to provide as complete coverage as possible since linkage disequilibrium can vary dramatically across even very short distances within a gene. Analyses of these data used the Pedigree Disequilibrium Test for single markers and a multilocus likelihood ratio test.


RESULTS
As expected, linkage disequilibrium occurred within each of these genes but we did not observe significant LD across genes. None of the polymorphisms in NRCAM, LRRN3, or KIAA0716 gave p < 0.05 suggesting that none of these genes is associated with autism susceptibility in this subset of chromosome 7-linked families. However, with LAMB1, the allelic association analysis revealed suggestive evidence for a positive association, including one individual SNP (p = 0.02) and three separate two-SNP haplotypes across the gene (p = 0.007, 0.012, and 0.012).


CONCLUSIONS
NRCAM, LRRN3, KIAA0716 are unlikely to be involved in autism. There is some evidence that variation in or near the LAMB1 gene may be involved in autism.
Hutcheson
Holli B
HB
Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37027, USA. hutcheso@ncifcrf.gov
Olson
Lana M
LM
Bradford
Yuki
Y
Folstein
Susan E
SE
Santangelo
Susan L
SL
Sutcliffe
James S
JS
Haines
Jonathan L
JL
D001321:Autistic Disorder / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics; D005192:Family Health; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D015815:Cell Adhesion Molecules; D005819:Genetic Markers; C491152:NRCAM protein, human