Genetic Epidemiology

Research Interests

Our main research interest is the genetic basis of complex traits, with a major focus on behavioral pathologies such as autism spectrum disorders. Autism is a chronic behavioral disorder characterized by deficiencies in social interaction, verbal and non-verbal communication and repetitive and stereotyped behaviors, and by a wide variability in symptom severity among patients. Although educational/behavioral intervention and pharmacological therapy can be sometimes helpful, they do not represent a cure for this disorder. The pathophysiology of autism is not understood, but the familiar aggregation of the disease and of other disorders in the spectrum are strong indicators of a genetic contribution, with the involvement of multiple genes.

Group Members

Research Project

Genetic Epidemiology of Autism

The main objective of this project is the identification and characterization of susceptibility factors predisposing to autism spectrum disorder. A multidisciplinary team, including scientists, clinicians, psychologists and educators, working from several locations, namely the IGC, the HP in Coimbra and the HDES in S. Miguel, Azores, contributes to the development of the study. For this project, this team has established a database for autism spectrum disorders that includes extensive clinical information, behavior evaluations, biochemical measurements and DNA genotypes from patients and their families. In this context, several main questions are being investigated. One question concerns the genetic epidemiology of autism spectrum disorders in Portugal. An epidemiological survey for ASD as been carried out, with the aim of determining the prevalence in mainland Portugal and the Azores, estimate disease risk for relatives and collect data on the present health and educational situation of autistic children in Portugal. Analysis of the data collected in this survey yielded some findings of particular interest: 1) analysis of the most relevant clinical correlates of ASD in our population has shown that there is an unexpectedly high prevalence of mitochondrial disorder in autistic children; 2) the prevalence of autism in the Azores islands, a geographically isolated group of islands in the Atlantic Ocean, is 50% higher than in mainland Portugal; 3) a very high incidence of cognitive and neuropsychiatric disorders is observed in many of the studied families. Studies are being carried out to further our understanding of these issues, namely the role of nuclear genes encoding mitochondrial proteins in autism and the hypothesis of a common genetic basis underlying the heterogeneous expression of cognitive/psychiatric disease in families with autism. Candidate genes and candidate gene regions for autism spectrum disorders and disease-associated phenotypes are being tested in our sample. Hyperserotonemia in a proportion of autism patients is one of the few consistent findings in the pathophysiology of autism, and has been shown to aggregate in families. We have found that variants of the serotonin transporter gene significantly contribute to hyperserotonemia in autism, and believe that the serotonin transporter gene is involved in disease etiology in the subset of patients with hyperserotonemia. We also find that other serotonin-related genes contribute to this phenotype. Given that autism is a phenotipically complex disease, likely determined by the conjunction of common variants from multiple genes, we have been emphasizing the importance of developing statistical methods that incorporate multiple parameters in the definition of the phenotype, as well as methods that assess the interactions between multiple genes for specific quantitative phenotypes such as serotonin levels or behavioral measurements. We also emphasize the characterization of endophenotypes. For instance, we have been exploring the hypothesis of an autoimmune dysfunction in autism, and have found that autoimmune reactivities occur significantly more often in autistic patients, possibly arising in consequence of a CNS insult occurred earlier in development. Recently we have recently joined the Autism Genome Project, a consortium led by the National Alliance for Autism Research, that brings together more than 150 worldwide scientists in an unprecedented effort for the identification of the genes for autism.

Funding

POCTI/ESP/39636/2001
Genetic Epidemiology of autism

Collaborators

Universidade de Braga, Braga
Patricia Maciel

Hospital Pediatrico de Coimbra, Coimbra
Guiomar Oliveira

City of Hope National Medical Center, Duarte, CA, USA
Steve Sommer,

Trinity College, Dublin, Ireland
Louise Gallagher

Vanderbilt University, Nashville, TN, USA
James Sutcliffe

Hospital do Divino Espirito Santo, Ponta Delgada, Açores
Luisa Mota Vieira

Research Project

Pharmacogenetics of risperidone therapy in autism spectrum disorders

The objective of this project is the identification of genetic factors underlying the variability in response to therapy with the atypical antipshycotic risperidone, observed in autistic children. The hypothesis is that this individual variability in response, as well as in the occurrence of side effects, is determined by multiple parameters among which genetic factors have a major impact. The possibility of predicting individual response based on specific genotypic information will have a major importance for therapeutic decisions in clinical settings.

Funding

POCTI/FCB/44706/2002
Pharmacogenetics of risperidone therapy in autism spectrum disorders

Collaborators

Hospital Pediatrico de Coimbra, Coimbra
Guiomar Oliveira

Research Project

Genetics of Human Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder with a wide range of clinical manifestations and characterized by multiple organ systems involvement, polyclonal B cell activation and production of autoantibodies against nuclear, cytoplasmic and cell surface antigens. It is a multifactorial disorder, in which genetic susceptibility plays an important role, with multiple genes involved. In the present project we aim at the identification of genetic susceptibility factors involved in the etiology and pathophysiology of SLE. The objective of this work is the identification and characterization of disease-associated phenotypes and subsequent genetic mapping. Clinical patterns, prevalence of different types of autoantibody repertoires, lymphocyte physiology and the involvement of regulatory T cells are being investigated in patients and their relatives. Interesting SLE-associated phenotypes segregating in the affected families have been defined, and candidate genes and chromosomal regions contributing to the determination of such phenotypes are now being analyzed.

Collaborators

ICBAS
Berta Martins

Hospital de Santa Maria, Lisboa
Carlos Ferreira

Hospital do Divino Espirito, Açores
Luisa Mota Vieira

Associação de Doentes com Lupus

Hospital de S. João
Carlos Vasconcelos

Hospital de Sta. Cruz, Lisboa
João Faro Viana

Publications

Coutinho, A.M., Oliveira, G., Morgadinho, T., Fesel, C., Macedo, T.R., Bento, C., Marques, C., Ataíde, A., Miguel, T., Borges, L., Vicente, A.M. (2004). Variants of the Serotonin Transporter Gene (SLC6A4) Significantly Contribute to Hyperserotonemia in Autism. Molecular Psychiatry 9(3) :264-271

Barreto, M., Santos, E., Ferreira, R., Fesel, C., Fontes, F., Pereira, C., Martins, B., Andreia, R., Viana, J.F., Crespo, F., Vasconcelos, C., Ferreira, C. and Vicente, A.M. (2004). Evidence for CTLA4 as a susceptibility gene for Systemic Lupus Erythematosus. European Journal of Human Genetics (in press)

Silva, S., Correia, C., Fesel, C., Coutinho, A.M., Barreto, M., Marques, C., São-Miguel, T., Ataide, A., Bento, C., Borges, L., Oliveira, G., Vicente, A.M. (2004). Autoantibody repertoires to brain tissue in autism spectrum disorders. Journal of Neuroimmunology (in press)

Oliveira, G., Diogo, L., Grazina, M., Garcia, P., Borges, L., Vicente, A.M., Oliveira, C.R. (2004). Mitochondrial Dysfunction in Autism Spectrum Disorders – evidence for the association of a mitochondrial respiratory chain functional abnormality with autism. Developmental Medicine and Child Neurology (submitted)

Muglia, P., Vicente, A.M., Verga, M., King, N., Macciardi, F., Kennedy, J.L. (2003). Association between the BDNF gene and schizophrenia. Molecular Psychiatry 8(2) :146-147

Wong, A.H.C., Macciardi, F., Klempan, T., Kawczynski, W., Barr, C.L., Lakatoo, S., Wong, M., Buckle, C., Trakalo, J., Boffa, E., Oak, J., Azevedo, M.H., Dourado, A., Coelho, I., Macedo, A., Vicente, A., Valente, J., Ferreira, C.P., Pato, M.T., Pato, C.N., Kennedy, J.L. & Van Tol, H.H.M. (2003). Identification of candidate genes for psychosis in rat models, and possible association between schizophrenia and the 14-3-3 gene. Molecular Psychiatry 8(2) :156-166

Oliveira, G., Matoso, E., Vicente, A.M., Ribeiro, P., Marques, C., Ataíde, A., São-Miguel, T., Saraiva, J., Carreira, I. (2003). Partial Tetrasomy of chromosome 3q mosaicism in a child with autism. Journal of Autism and Developmental Disorders 33(2) :177-185

Vicente, A.M., Coutinho, A.M., Mota-Vieira, L., Marques, C., Oliveira, G. (2000). Genetic variation of serotonin system genes in a sample of autism families form Portugal. Am J Hum Genet 67(4) :Supp.2:303

Petronis, A., Timinskas, A., Basile, V., Vicente, A.M., Janulaitis, A., Kennedy, J.L. (1999). A novel PCR-RFLP detection method using an optimized set of restriction enzymes. Neuromethods 34 In Vitro Neurochemical Techniques. Boulton AA, Baker GB (eds.). Humana Press, Totowa, New Jersey

Basile, V., Vicente, A.M., Martignetti, J.A., Skryabin, B.V., Brosius, J., Kennedy, J.L. (1998). Assignment of the human BC200 RNA gene (BCYRN1) to chromosome 2p16 by radiation hybrid mapping. Cytogenet Cell Genet 82(3-4) :271-2

Vicente, A.M. and Kennedy, J.L. (1997). Molecular Genetics of Neurodevelopment and Schizophrenia. In: Neurodevelopmental Models of Adult Psycopathology Keshavan MS and Murray RM (eds). Cambridge University Press, London

Vicente, A.M., Verga, M., Macciardi, F., Bassett, A., Honer, W., Bean, G., Kennedy, J.L. (1997). NCAM and schizophrenia: genetic studies. Molecular Psychiatry 2 :65-69

Vicente, A.M. and Ambrósio, A. (1997). Genetic strategies in schizophrenia research Psiquiatria Clínica 18(1) :25-34

Vicente, A.M., St.George-hyslop, P., Macciardi, F., Sorbi, S., Mortilla, M., Rogaev, E., Heggart, D., Kennedy, J.L. (1993). Evaluation of APP codon 713 in schizophrenia and Alzheimer's disease. Psychiatric Genetics 3 :223-225