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This article is part of the supplement: Beyond the Genome 2012

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Extended homozygous haplotypes at genes involved in brain development associated with autism

Ping-I Lin

  • Correspondence: Ping-I Lin

Author Affiliations

Division of Biostatistics and Epidemiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA

BMC Proceedings 2012, 6(Suppl 6):P24  doi:10.1186/1753-6561-6-S6-P24

The electronic version of this article is the complete one and can be found online at:

Published:1 October 2012

© 2012 Lin; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Recent evidence has suggested that extended homozygous haplotypes (EHH) in several genomic regions may be associated with risk of psychiatric disorders (for example, schizophrenia). The phenomenon of EHHs may arise from recent positive selection, inbreeding, as well as recessive models.

Materials and methods

We used Affymetrix 500K SNP arrays to search for EHH in 1,385 affected individuals and 1,498 unaffected individuals. The EHH was defined as at least 100 contiguous homozygous SNPs. To interrogate the associations between EHHs and autism, logistic regression analysis with generalized equation estimation model to adjust for intrafamily correlation was performed. We also examined if any of the associated EHHs were related to deletions by examining the data of copy number variants. Finally, we checked if any associated EHHs contained genes with signatures of recent positive selection in the Hapmap sample. We used the Sidak method to correct for multiple tests.


The best finding was obtained at the HMLGCL1 gene (P = 3 × 10–5, odds ratio 0.15). The HMLGCL1 gene has been found to be highly expressed in some brain regions. Other genes harbored in regions enriched with EHHs associated with autism include ZFP91, CNTF, NAPL1 and TLE4. We also used the webtool Panther to assess if this set of genes is over-represented in any pathways. The results suggest that these genes collectively may be involved in the Wnt signaling pathway and neurodevelopment process. No remarkable evidence for recent positive selection was obtained for most of these loci, except the TLE4 gene (P = 0.008).


Taken together, these genes involved in brain development may harbor variants that exert a recessive effect on the risk of autism. Further work is warranted to replicate these findings in other populations.