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DRD2 and PPP1R1B (DARPP-32) Hettinger et al. Behavioral and Brain Functions 2012, 8:19 http://www.behavioralandbrainfunctions.com/8/1/19 RESEARCH Open Access DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families Joe A Hettinger1, Xudong Liu2,3, Melissa L Hudson2,3,4, Alana Lee2,3,4, Ira L Cohen4,5, Ron C Michaelis6, Charles E Schwartz7, Suzanne ME Lewis4,8,9 and Jeanette JA Holden1,2,3,4,10,11* Abstract Background: The neurotransmitter dopamine (DA) modulates executive functions, learning, and emotional processing, all of which are impaired in individuals with autism spectrum disorders (ASDs). Our previous findings suggest a role for dopamine-related genes in families with only affected males. Methods: We examined two additional genes which affect DA function, the DRD2 and PPP1R1B (DARPP-32) genes, in a cohort of 112 male-only affected sib-pair families. Selected polymorphisms spanning these genes were genotyped and both family-based and population-based tests were carried out for association analysis. General discriminant analysis was used to examine the gene-gene interactions in predicting autism susceptibility. Results: There was a significantly increased frequency of the DRD2 rs1800498TT genotype (P = 0.007) in affected males compared to the comparison group, apparently due to over-transmission of the T allele (P = 0.0003). The frequency of the PPP1R1B rs1495099CC genotype in affected males was also higher than that in the comparison group (P = 0.002) due to preferential transmission of the C allele from parents to affected children (P = 0.0009). Alleles rs1800498T and rs1495099C were associated with more severe problems in social interaction (P = 0.0002 and P = 0.0016, respectively) and communication (P = 0.0004 and P = 0.0046), and increased stereotypic behaviours (P = 0.0021 and P = 0.00072). General discriminant analysis found that the DRD2 and PPP1R1B genes additively predicted ASDs (P = 0.00011; Canonical R = 0.26) and explain ~7% of the variance in our families. All findings remained significant following corrections for multiple testing. Conclusion: Our findings support a role for the DRD2 and PPP1R1B genes in conferring risk for autism in families with only affected males and show an additive effect of these genes towards prediction of affected status in our families. Keywords: Autism spectrum disorders, Dopamine receptors, DARPP-32, Association study, Candidate gene * Correspondence: [email protected] 11Autism Research Program/Genetics and Genomics Research Laboratory, Ongwanada Resource Centre, 191 Portsmouth Ave, Kingston, ON, Canada K7M 8A6 Full list of author information is available at the end of the article © 2012 Hettinger et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hettinger et al. Behavioral and Brain Functions 2012, 8:19 Page 2 of 13 http://www.behavioralandbrainfunctions.com//8/1/19 Introduction The DRD2 gene comprises eight exons [19] and maps Autism spectrum disorders (ASDs) are characterized by re- to 11q22-q23 [20]. It encodes the dopamine D2 receptor petitive behaviours and interests, as well as deficiencies in which, in addition to its role in postsynaptic neurons, communication and social interaction. They are believed acts as an autoreceptor mediating DA synthesis [21] and to be complex, polygenic disorders predominantly charac- neurotransmission [22] in DAergic neurons. The dopa- terized by multifactorial inheritance [1], although Zhao mine D2 receptor is involved in the DAergic modulation et al. [2] (2007) suggested that Mendelian inheritance may of executive functions [23], reversal learning [24] and apply to autism risk in a subgroup of families with affected emotional processing [25]. Drd2−/− mice have abnormal males. To address the significant genetic heterogeneity and gait similar to that of individuals with Parkinson disease phenotypic variation seen among affected individuals, [26], and the administration of antipsychotic medications which has confounded the conclusive identification of can- (e.g., risperidone, a dopamine D2 receptor antagonist) didate genes for the majority of cases, we have been testing has proven efficacious in treating symptoms associated genes for evidence of association with specific ASD endo- with ASDs [27]. phenotypes in an effort to identify a subgroup within the The PPP1R1B gene, located at chromosome 17q12 and ASD population whose members share an underlying comprising 7 exons (http://www.ncbi.nlm.nih.gov; Gen- pathophysiology. eID 84152), encodes DARPP-32, which is expressed in Abnormalities in neurotransmitter pathways can ac- dopaminoceptive (DAceptive) neurons [28] and mediates count for the deficits seen in persons with ASDs. In con- the effects of both D1 and D2 dopamine receptor classes trast to the attention which has been directed to the [29]. For example, dopamine D2 receptor antagonist- study of genes involved in the glutamate [3], GABA [3] induced catalepsy in rats is attenuated in Ppp1r1b−/− and serotonin pathways [1], genes related to the synthe- mice [30] and knockout mice are impaired in reversal sis, function and metabolism of dopamine (DA) have learning [31]. Genetic [32,33] and immunoblot [34] stud- received little attention [4]. ies showed an association of PPP1R1B with altered PFC We have argued [5] that genes in the dopaminergic DARPP-32 protein levels in schizophrenia and bipolar (DAergic) pathway are excellent candidates based on disorder, two conditions for which DA dysfunction is evi- their affect on ASD behaviours. DA modulates motor dent and which exhibit comorbidity with autism [35]. functions [6], cognitive processes (including executive There are two previous studies which examined the functions [7] and learning [8]), and emotional regulation DRD2 gene as a candidate gene for autism. The first [36] [9] - all of which are abnormal in individuals with autism reported an increased frequency of the TaqI A1 allele in [10-13]. DA also plays a role in social interactions [14] persons with autism (N = 33) compared to controls and the pathophysiology of stereotypies [15]; impair- (N = 314), whereas the second [37] found no evidence for ments in social interaction and the presence of increased transmission disequilibrium of an intragenic microsatel- stereotypies are core features of autism. Furthermore, lite in 39 affected sib-pair families. No association studies there is decreased DAergic activity in the medial pre- have examined the role of PPP1R1B as a candidate gene frontal cortex (PFC) in children with autism [16], and for ASDs. increased levels of the major metabolite of DA, homova- Based on our hypothesis that DA-related genes are im- nillic acid (HVA), in cerebrospinal fluid from affected portant in male-only affected sib-pair families [18], we children compared to controls [17], indicating altered examined four markers at the DRD2 locus that are com- DAergic function in these individuals. monly used to investigate possible associations between Based on our earlier findings on the dopamine β- DAergic function and behavioural abnormalities [38], hydroxylase (DBH) gene, which encodes the enzyme that and three polymorphisms at the PPP1R1B locus to deter- converts DA to norepinephrine, in mothers from male- mine whether there was an association of these DA- only affected sib-pair families [18], we have pursued a related genes with autism. comprehensive study of DA-related genes in mothers and sons with ASDs. Since our initial study with DBH, in Materials and methods which we found an increased frequency of the 19-bp de- Subjects letion in mothers from male-only affected sib-pair fam- The 112 affected sib-pair families and the comparison ilies [18], we identified a 3-marker risk haplotype in the group (N = 443) were previously described [5]. Briefly, dopamine D1 receptor (DRD1) gene [5] in our family co- the study group included 28 families from Canada [18], 5 hort having only affected sons. Here we report our find- from the South Carolina Autism Project [39], and 79 ings on two other genes affecting DA levels and families obtained through the Autism Genetic Resource function, the dopamine D2 receptor (DRD2) and protein Exchange (AGRE) in the United States [40]. All families phosphatase 1, regulatory subunit 1B (PPP1R1B) genes, have two or more children with either autism or an and results of tests for gene-gene interactions. ASD, including Asperger syndrome and pervasive Hettinger et al. Behavioral and Brain Functions 2012, 8:19 Page 3 of 13 http://www.behavioralandbrainfunctions.com//8/1/19 developmental disorder (PDD) variants. This study was disorders. Primer sequences, PCR and digestion condi- approved by the Queen’s University Research Ethics tions are shown in Table 1. All PCR reactions were car- Board and written informed consent was obtained from ried out using 5 ng of template DNA; digestion products parents of all participating families from Canada and were separated on either 2% (rs1079597, rs1800498 and South Carolina, and through AGRE [40]. rs1800497) or 2.5% (rs1799732) agarose gels and visua- All 443 samples from the comparison group (blood- lized using ethidium bromide and UV illumination. In spots from anonymous newborns taken for the purpose
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