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Dense linkage disequilibrium mapping in the 15q11–q13 maternal expression domain yields evidence for association in autism

Molecular Psychiatry volume 8, pages 624–634 (2003)Cite this article

Abstract

Autism [MIM 209850] is a neurodevelopmental disorder exhibiting a complex genetic etiology with clinical and locus heterogeneity. Chromosome 15q11–q13 has been proposed to harbor a gene for autism susceptibility based on (1) maternal-specific chromosomal duplications seen in autism and (2) positive evidence for linkage disequilibrium (LD) at 15q markers in chromosomally normal autism families. To investigate and localize a potential susceptibility variant, we developed a dense single nucleotide polymorphism (SNP) map of the maternal expression domain in proximal 15q. We analyzed 29 SNPs spanning the two known imprinted, maternally expressed genes in the interval (UBE3A and ATP10C) and putative imprinting control regions. With a marker coverage of 1/10 kb in coding regions and 1/15 kb in large 5′ introns, this map was employed to thoroughly dissect LD in autism families. Two SNPs within ATP10C demonstrated evidence for preferential allelic transmission to affected offspring. The signal detected at these SNPs was stronger in singleton families, and an adjacent SNP demonstrated transmission distortion in this subset. All SNPs showing allelic association lie within islands of sequence homology between human and mouse genomes that may be part of an ancestral haplotype containing a functional susceptibility allele. The region was further explored for recombination hot spots and haplotype blocks to evaluate haplotype transmission. Five haplotype blocks were defined within this region. One haplotype within ATP10C displayed suggestive evidence for preferential transmission. Interpretation of these data will require replication across data sets, evaluation of potential functional effects of associated alleles, and a thorough assessment of haplotype transmission within ATP10C and neighboring genes. Nevertheless, these findings are consistent with the presence of an autism susceptibility locus in 15q11–q13.

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Acknowledgements

This work was supported by an award from the National Alliance for Autism Research and NIH grant MH61009 to JSS and grant MH55135 to SEF. ELN is supported by the Medical Scientist Training Program at VU. Grant MH55284 to Joseph Piven supported recruitment of the 27 singelton families through the University of Iowa CLSA site. We acknowledge the contributions of the Vanderbilt Program in Human Genetics DNA Resources Core in providing materials for this study.

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Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Program in Human Genetics, Vanderbilt University, Nashville, TN, USA

    E L Nurmi, T Amin, L M Olson, J L McCauley, A Y Lam, E L Organ, J L Haines & J S Sutcliffe

  2. Center for Molecular Neuroscience, Vanderbilt University, Nashville, TN, USA

    E L Nurmi, M M Jacobs, J L Haines & J S Sutcliffe

  3. Department of Psychiatry, Tufts University School of Medicine and New England Medical Center, Boston, MA, USA

    S E Folstein

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  1. E L Nurmi
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Correspondence to J S Sutcliffe.

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Nurmi, E., Amin, T., Olson, L. et al. Dense linkage disequilibrium mapping in the 15q11–q13 maternal expression domain yields evidence for association in autism. Mol Psychiatry 8, 624–634 (2003). https://doi.org/10.1038/sj.mp.4001283

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