Resumo

MARTINEZ-LEVY, Gabriela Ariadna; VASQUEZ-MEDINA, Josué Alberto  e  CRUZ-FUENTES, Carlos Sabás. Genome diversity of the Mexican Mestizo population: Scopes and perspectives for develop Genetic Psychiatric Research. Salud Ment [online]. 2010, vol.33, n.3, pp.273-280. ISSN 0185-3325.

A few months ago the paper entitled <<Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico>> by Solezzi et al. was published in the Proceedings of the National Academy of Medicine USA. Beyond its genuine scientific merits, we consider important to comment and discuss it, as some of their scopes and implications have caused not only a wide interest but also some concern in the scientific community and in society as a whole. We focused particularly in the possible impact that it could have in the development of psychiatric genetics in Mexico and Latin America. Firstly, a brief recapitulation of the published work is showed, and its principal data are discussed on the ground of the specialized literature. What is the background of this study and why it is important to develop a HapMap of the Mexican population? It is well known that most of the complex diseases, as is the case for psychiatric conditions, have an important genetic associated component. It is expected that the identification of these genetic factors will be of the most importance in the understanding of etiology, diagnosis, prognosis and therapeutic improvement for psychiatric medicine. The information provided by the collection of millions of single nucleotide polymorphisms (SNPs) has been used to develop the so-called international haplotype map (HapMap) Project. The human haplotype blocks catalog allows an important reduction in the number of SNPs that are necessary to perform linkage and genetic association studies, mainly those of the Genome Wide Association Studies (GWAS) category. However, it is recognized that the frequency of these polymorphisms differs significantly among ethnic groups; so the data published by Solezzi et al. are aimed to develop a HapMap particularly oriented to the Mexican mestizo population. This information will be of outstanding importance in studies including Mexican subjects in order to select the most informative group of SNPs and also to control for possible population stratification flaws. However, achievement of these objectives will need much more work to be done, as for example should it be mandatory to analyze a greater number of polymorphisms, develop genome re-sequenciation projects and include other Mexican subpopulations in the analysis. How this results will help psychiatric genetics in Mexico? As noted above, there is substantial evidence that genetics plays an important influence in the phenotypic expression of mental disorders; however, the effort to identify the specific genetic variants associated with psychiatric conditions has not been very successful. Although multiple reasons could be invoked related to this limited success, here we focus in two specific topics. The first one is related to the candidate gene approach in genetic association studies, in which researchers based on a logic scientific hypothesis evaluate specific genetic variants putatively related to the disorder of interest (i.e. the candidate genes hypothesis). However, the possibility of identification of the associated genetic risk variants is importantly reduced, as the knowledge about complex disorders and particularly those related with mental problems is mostly incomplete. The continuous advances in neurobiological and psychological knowledge provides hope for future improvement and the generation of new ideas. On the other hand, the alternative and technically feasible approach to analyze simultaneously hundred of thousands, even millions, of genetic variants all along the human genome with no regarding of a priori candidate genes (as in the Genome Wide Association Studies, GWAS), has reached the psychiatric genetics arena. In this regard, it is worth noting that several published studies of GWAS and psychiatric disorders have recently appeared and have contributed to develop important clues. Particularly interesting are those pointing out to the until recently unexplored role of Copy Number Variants (CNVs) associated to some forms of autism and schizophrenia. It is worth noting that most GWAS are based in the common disorder-common variant hypothesis (where genetic polymorphisms studied have a frequency >5% in the general population). However, the alternative view of the common disorder-rare variant hypothesis have also been proposed. As most of the rare SNPs have not been identified in the current effort of the HapMap project, a re-sequenciation analysis of human genomes of particular ethnic groups seems to be mandatory. The other relevant issue is related to the following question: Are current psychiatric diagnostic categories proper phenotypes for the study of genetic aspects associated with mental disorders? Diagnosis in psychiatry is based mainly in the identification and interpretation from clinicians of the patient´s cardinal symptoms. However, overlapping of symptoms between nosological categories, comorbidity and changes in natural history of the disorder associated or not to therapeuthical improvements are issues hampering efforts in psychiatric genetics. At this point it is important to recall that psychiatric diagnostic categories have evolved along the last four or five decades after intense discussion among experts. However, even recognizing the clinical virtues of current consensus (integrated for example in the DSM-IV-R), it is clear that is still a pending issue, awaiting the most recent contributions from different areas of knowledge, including genetics. Moreover, unlike other complex disorders like hypertension or diabetes, where use of clinical and relevant phenotypes, such as blood pressure and levels of blood glucose, can increase the power of genetic analysis, in mental disorders this kind of quantitative phenotypes are rare or unknown, which restrains the process to find genetic variants associated with psychiatric disorders, independently of the study design and the technology of analysis. In brief, in countries as ours, composed mainly by mestizo population, is of the utmost importance for molecular genetics studies to obtain specific information about its genetic composition. In this sense, the National Institute of Genomic Medicine has made an important contribution; however, and as correctly stated by Solezzi et al., <<much more work needs to be done>>. We argue that the even the deepest knowledge in genetic variation or use of state-of-the-art technology is not enough to boost the development of psychiatric genetics research. Re-evaluation of current clinical phenotypes and/or identification of new and relevant intermediate or endo- phenotypes in psychiatry are no less important. Additionally, it will be necessary to integrate to the complex equation of the genetics of complex disorders the seminal role of <<environment>>. In this respect we are strong advocates of multidisciplinary research as the clue for better understanding the etiology of mental disorders. Finally, we hope this work will help to elucidate some of the questions and concerns originated from the published article by Silva-Solezzi et al.

Palavras-chave : Genome; HapMap; Mexican; polymorphisms; psychiatry; complex disorders.

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