Protocadherin α (PCDHA) as a novel susceptibility gene for autism

Protocadherin α (PCDHA) as a novel susceptibility gene for autism

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J Psychiatry Neurosci 2013; 38(3): 192-198

Ayyappan Anitha, PhD;* Ismail Thanseem, PhD;* Kazuhiko Nakamura, MD, PhD;* Kazuo Yamada, MD, PhD; Yoshimi Iwayama, MS; Tomoko Toyota, MD, PhD; Yasuhide Iwata, MD, PhD; Katsuaki Suzuki, MD, PhD; Toshiro Sugiyama, MD, PhD; Masatsugu Tsujii, MA; Takeo Yoshikawa, MD, PhD; Norio Mori, MD, PhD

Anitha, Suzuki, Tsujii, Mori — Research Center for Child Mental Development, Hamamatsu University School of Medicine; Thanseem, Nakamura, Iwata, Mori — Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu; Yamada, Iwayama, Toyota, Yoshikawa — Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako; Sugiyama — Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, Hamamatsu; Tsujii — Faculty of Sociology, Chukyo University, Toyota, Japan

*These authors contributed equally to this work.


Background: Synaptic dysfunction has been shown to be involved in the pathogenesis of autism. We hypothesized that the protocadherin α gene cluster (PCDHA), which is involved in synaptic specificity and in serotonergic innervation of the brain, could be a suitable candidate gene for autism.

Methods: We examined 14 PCDHA single nucleotide polymorphisms (SNPs) for genetic association with autism in DNA samples of 3211 individuals (841 families, including 574 multiplex families) obtained from the Autism Genetic Resource Exchange.

Results: Five SNPs (rs251379, rs1119032, rs17119271, rs155806 and rs17119346) showed significant associations with autism. The strongest association (p < 0.001) was observed for rs1119032 (z score of risk allele G = 3.415) in multiplex families; SNP associations withstand multiple testing correction in multiplex families (p = 0.041). Haplotypes involving rs1119032 showed very strong associations with autism, withstanding multiple testing corrections. In quantitative transmission disequilibrium testing of multiplex families, the G allele of rs1119032 showed a significant association (p = 0.033) with scores on the Autism Diagnostic Interview–Revised (ADI-R)_D (early developmental abnormalities). We also found a significant difference in the distribution of ADI-R_A (social interaction) scores between the A/A, A/G and G/G genotypes of rs17119346 (p = 0.002). Limitations: Our results should be replicated in an independent population and/or in samples of different racial backgrounds.

Conclusion: Our study provides strong genetic evidence of PCDHA as a potential candidate gene for autism.

Submitted Apr. 3, 2012; Revised June 7, 24, 2012; Accepted June 26, 2012..

Acknowledgements: We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (23591700 to A. Ayyappan and 23390288 to K. Nakamura). We thank Tae Takahashi for technical assistance.

Competing interests: As above for A. Ayyappan and K. Nakamura; none declared for all others.

Contributors: A. Ayyappan, I. Thanseem, K. Nakamura, T. Sugiyama, M. Tsujii, T. Yoshikawa and N. Mori designed the study. K. Yamada, Y. Iwayama, T. Toyota, Y. Iwata and K. Suzuki acquired the data; A.Ayyappan, I. Thanseem, K. Nakamura, K. Yamada, Y. Iwayama and T. Toyota analyzed it. A. Ayyappan, I. Thanseem and K. Nakamura wrote the article. All authors reviewed the article and approved its publication.

DOI: 10.1503/jpn.120058

Correspondence to: K. Nakamura, Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, 1-20-1 Handayama,
Hamamatsu, Higashi-ku, Shizuoka 431-3192, Japan;