Virginia Rodriguez Funes, MD, FACS El Salvador

Background  The Latin American population it is now the largest single ethnic group in the United States, which makes it a timely population for genetic study,  It has been largely untapped in previous genetic studies of PD and,  It has more individuals per family than other ethnic groups, and has genetic isolates which may aid in the fine-mapping of susceptibility loci identified from initial genome screens.

 This study proposes the sample collection, genotyping and analysis necessary to localize genes that contribute to PD genesis and quantitative traits associated with PD in this population.  The long term goals, beyond the scope of this study are to fine map and identify mutations in specific genes associated with loci identified in the course of this current project.

1. Psychiatric disorders (PD):  Affect quality of life for the individuals and families  Contribute to high annual public health costs  Are of high prevalence in all populations studied 2. Difficulty finding genetic loci that are involved in PD derived from the complex nature of the illness. No study has shown predominant linkage to just one site in their sample, even when the sample is drawn from a more homogenous population.

3. Key obstacles to mapping PD gene loci:  Ethiological heterogeneity  Imprecision in the definition of affected phenotypes  Uncertainty regarding mode of genetic transmission

Psychiatric investigators, health care providers and government officials have all identified ethnic disparities in mental health treatment as a significant US public health problems.

Rationale 1. To overcome this obstacle: Collect samples from very large families, consistingly of rigorously diagnosed PD individuals, drawn from genetically homogeneous populations. 2. Some studies have shown recent advances in identifying genes for specific PD in very narrow diagnostic classification. The PD studied in this project is currently at a similar stage

The researchers project enhanced potential to identify genes involved in the pathogenesis of PD in the Latino population, by defining endophenotypes and quantitative traits that are associated with PD in the pedigrees which will constitute this study.

How to identify endophenotypes  By collecting neuropsychological data on probands and their families, with an extension to second and third degree relatives, in a subset of X number of pedigrees.

For a cognitive measure or any marker to be considered, an endophenotype must show:  High heritability  Association with the illness  Presence independent of the clinical state  Cosegregate with the illness within a family  Non-affected family members must show impairment on this measure.

Methodology  Local researchers from Mexico and Central America will be trained in the US with specific tools for accurate psychiatric diagnosis  Local researchers will collect the families in 6 mesoamerican countries: recruiters will identify PD diagnosed subjects in inpatient and outpatient units in psychiatric hospitals and with media advertisement

Identified patient vital data will be collected in an Excel database, then will prioritize those under 40 years of age. Then will contact them and obtain preliminary informed consent, to get data, such as, presence of siblings with the illness and verification that four grandparents are from mesoamerican ancestors. When the family meets the inclusion criteria and agrees to participate, the psychiatric diagnostic tools will be used on the patient and the affected sibling and neuropsychological assessment will be conducted in all members of the family.

The ideal family to be recruited would be:  PD sibling pairs  Parents  An average of two unaffected siblings. Unaffected or affected siblings can be from age 15 up. X number of pedigrees averaging 20 subjects per pedigree

All subjects affected and non-affected will: 1. Give samples of DNA 2. MRI tests 3. Perform clinical and neuropsychological testing.  Gene samples will be sent to a central Universities in the US and analyzed with special softwares  Then, gene samples will be banked in a central gene bank in the US and will be shared with other researchers as an unfinishible source of DNA

Cell cultures will be maintained in this central bank in the US and will be made available to qualified researchers at the end of this project. Genes will be dissociatied from ID. Family relationship information, ethnicity, and all clinical and genotype data will be included in the database. DNA will be placed in the public domain, they will be available to investigators to use in projects that are unrelated to the present one and may even be put to commercial use.

The participants will be informed of these possibilities in the narrative summary and will be made aware that they will have no rights to any subsequent use of the materials.

First question Do you find any ethical issues with the proposed logic for overcoming the failures in identifying genes loci associated with the pathogenesis of PD?

Second question How would you categorize the potential population to the sponsor, and the principal researchers.

Third question Do you think the rational for population selection is free of bias (descrimination)?

Fourth question How would you classify the risk of participation of this population?

Fifth question Do you think the whole study shoud be adjusted to the Universal Declaration of Genetic data recollection? How would you classify the autonomy of this population based on the way they were identified and recruited?