MAPBYADMIXTURECHL · Mapping Genes involved in Psychiatric Disorders by Admixture Linkage Disequilibrium in Chilean populations

Mapping genes involved in psychiatric disorders by admixture linkage disequilibrium in Chilean populations

Psychiatric and behavioural disorders present a complex pattern of inheritance with both genetic and environmental factors influencing disease risk. Comorbidity amongst these disorders represents an additional confounding element as well as the fact that the same genes may be underlying genetic susceptibility to a spectrum of psychiatric disorders; this complex pattern of inheritance complicates efforts to identify their contributing genetic susceptibility factors. In fact, despite the numerous existing association studies aiming to find genes involved in psychiatric phenotypes, just a few examples of links between gene variants and disease have been found. Furthermore, there are evident problems in the replication of positive associations amongst different studies, which reflects the complexity in the analysis of psychiatric disorders. Several factors could underlie this failure on replication such as difficulties on the definition of clinical phenotypes, the existence of distinct disease incidence or the degree of genetic differentiation among populations. One of the goals of the project was the construction of a panel of single nucleotide polymorphisms (SNPs) to be used for the mapping of disease susceptibility genes for psychiatric disorders in native (Aymara from Arica, north Chile) and recently admixed populations from Chile. In particular, this proposal was focused on the identification of genetic variants involved in attention-deficit hyperactivity disorder (ADHD), a common and highly disabling psychiatric disorder characterised by a persistent pattern of inattention and / or hyperactivity-impulsivity, and other related behavioural traits. We also planned to explore signals of population-specific selection in the studied populations and, finally, we aimed to assess the issue of whether the inconsistencies in replication studies involving candidate genes for ADHD could be explained by the degree of population genetic differentiation. As complementary goals, the project also sought to strengthen and consolidate a strong collaboration between the two institutions involved and to reinforce the management skills and leadership of the applicant. Description of the work performed and results The first critical phase of the project consisted on the collection of samples and the exhaustive phenotyping for behavioural traits and other socio-cultural relevant information for the study. A collection of samples from Aymara school children (n = 90) from Andean Highlands and mestizo school children from Santiago de Chile (n = 96) as well as a large sample of adults from mestizo population all around Chile (n = 600) was performed. A sample from Rapa-nui school children (n = 91) from Andean Easter Island was already available at the host institution. Phenotypic data was compiled through the application of the abbreviated Conners Scale for School Teachers (CST) and according to DSM-IV criteria, which allowed to score for each individual the total risk of ADHD and some of its components such as attention deficit (AD), hyperactivity and emotional problems (EP) amongst others. Depression, dysthymia, generalised anxiety disorder, social phobia, panic disorder, alcohol abuse and dependence, drugs abuse and dependence, posttraumatic stress disorder, and antisocial personality disorder was also assessed. A database with all the phenotypic data was constructed for the collected sample. As a second phase of the project genotyping and association analysis was performed. A panel of SNPs tagging candidate genes for ADHD was constructed and used for the genotyping of samples. Score ratings for ADHD components was performed and compared amongst the studied populations and association studies of ADHD with the DRD4 and SLCA3 polymorphisms were done. Analysis of the phenotypic data showed significant differences in score ratings for ADHD components among different populations, with the Easter populations presenting the highest risk for ADHD. Genetic association studies of the DRD4 VNTR showed that it is associated with ADHD in the Rapa-Nui population but not in the Mestizo and Aymara populations. These results are part of a manuscript (this Marie Curie International Outgoing fellowship has been properly acknowledged) that is press at the Revista Medica de Chile (Rothhammer F, Rothhammer P, Paz-Lagos L, Espinosa-Parrilla Y, Aboitiz F. Risk of attention deficit-hyperactivity disorder in Chilean school children of Andean and Polynesian origin. Relevance of 2R dopamine D4 receptor allele). Furthermore, we also explored the possible gene X gene interaction between SLC3A and DRD4 showing additive rather than epistatic effects of the DRD4 and SLC3A ADHD risk alleles (manuscript in preparation). We also studied and compared allele frequencies and haplotypes for polymorphisms in the DRD4 and SLC3A genes between the Chilean studied populations and other populations worldwide to look for signals of natural selection. Although we observed indications of possible positive selection for particular DRD4 alleles, unfortunately, we did not have enough statistical power to evidence this finding. Finally, we studied the role of genetic heterogeneity among human populations in the replicability of genetic association studies in ADHD as well as other associated disorders such as antisocial behaviour or substance abuse disorders in the adulthood. We measured the degree of population differentiation in SNPs tagging 22 genes previously associated with several psychiatric disorders among different world-wide populations and found a negative correlation between the replicability of studies associating genes to disease and the genetic differentiation between the studied populations (manuscript in preparation). Conclusions and potential socio-economic impact With the accomplishment of the project we expect to go deeper into the genetic basis of ADHD and other related psychiatric disorders (with the publication of at least three papers) particularly in native populations that have not been classically the focus of psychiatric genetics. This should contribute to increase our knowledge in population differentiation at the genotypic and phenotypic level. More specifically, from the social point of view, these investigations could help to better understand and improve educational performance of native children. Finally, it is worth to remark that this project has leaded to the establishment of a solid and fluent collaboration between both host laboratories and it has strengthened the leadership and management skills of the applicant.

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