Neurotransmitter systems and neurotrophic factors in autism: association study of 37 genes suggests involvement of DDC

Abstract

Objectives. Neurotransmitter systems and neurotrophic factors can be considered strong candidates for autism spectrum disorder (ASD). The serotoninergic and dopaminergic systems are involved in neurotransmission, brain maturation and cortical organization, while neurotrophic factors (NTFs) participate in neurodevelopment, neuronal survival and synapses formation. We aimed to test the contribution of these candidate pathways to autism through a case–control association study of genes selected both for their role in central nervous system functions and for pathophysiological evidences. Methods. The study sample consisted of 326 unrelated autistic patients and 350 gender-matched controls from Spain. We genotyped 369 tagSNPs to perform a case-control association study of 37 candidate genes. Results. A significant association was obtained between the DDC gene and autism in the single-marker analysis (rs6592961, P = 0.00047). Haplotype-based analysis pinpointed a four-marker combination in this gene associated with the disorder (rs2329340C–rs2044859T–rs6592961A–rs11761683T, P = 4.988e-05). No significant results were obtained for the remaining genes after applying multiple testing corrections. However, the rs167771 marker in DRD3, associated with ASD in a previous study, displayed a nominal association in our analysis (P = 0.023). Conclusions. Our data suggest that common allelic variants in the DDC gene may be involved in autism susceptibility.

Key words::

• Genetics
• autistic disorder
• serotonin
• dopamine
• DDC gene

Acknowledgements

We are grateful to all patients and controls for their participation in our study, to clinical collaborators (Montse Causi, Carlota Pont, Julia Ruiz, Inma Planelles, Mar Margalef, Mar Fernández, David Seguí and Blanca Gener) for patients’ assessment, to Lucía Madrigal for blood sampling, to Olaya Villa for cytogenetic analyses, to M. Dolors Castellar and others from the “Banc de Sang i Teixits” (Hospital Universitari Vall d’Hebron) for their collaboration in the recruitment of controls, to Mònica Gratacòs for her participation in the selection of part of the studied genes and polymorphisms, and to Miquel Casas for critical comments. Genotyping services were provided by the Spanish “Centro Nacional de Genotipado” (CEGEN; www.cegen.org). MR is a recipient of a Miguel de Servet contract from “Instituto de Salud Carlos III” (Spain) and CT was supported by fellowships from the Biomedical Network Research Centre on Rare Diseases (CIBERER) and the European Union (Marie Curie, PIEF-GA-2009-254930). Financial support was received from “Instituto de Salud Carlos III-FIS” (PI041267, PI042010, PI040524, RETICS G03/183, PI042209, PI041208 and PI070539), “Consejería de Innovación, Ciencia y Empresa”, Junta de Andalucía (CTS-546), “Fundació La Marató de TV3” (092010), Fundación Alicia Koplowitz and “Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR” (2009GR00971). These institutions had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Statement of Interest

L.A.P.J. is a member of the scientific advisory board of qGenomics. No other author reported any biomedical financial interests or potential conflicts of interest.