Human Genetics

Research Interests

Complex diseases, gene identification, neurological diseases, human genetics.

Group Members

Research Project

Genetics of familial stroke (STROKENETICS study)

The goal of this project is to create a stroke biobank to identify genes that influence the risk for developing stroke, also called susceptibility genes. Stroke is a “brain attack” cutting off vital blood and oxygen to the brain cells that control everything we do. Stroke is the third leading cause of death in the developed world. It is even more disabling than lethal, and the persistent neurological impairment and physical disability caused by stroke have a substantial socioeconomic cost. Stroke is a complex disease resulting from the interplay of environmental and genetic factors. Major known risk factors include family history, age, hypertension, hypercholesterolemia, diabetes, cardiovascular disease, smoking and alcohol consumption. Identification of genes increasing susceptibility to stroke would have far-reaching public health impact, from enhancing motivation to make behavioral and lifestyle changes in susceptible individuals to providing basic biological and clinical information about the development, prevention and treatment of stroke.

The genetic component has been demonstrated in twin and family studies, in animal model studies, and mutations have been found in several genes in rare classical Mendelian forms of stroke. However, very few susceptibility genes specific for the common forms of stroke have been identified and association studies have mostly reported conflicting results. We will use a novel genomic convergence approach that combines genomic screening, expression analysis, and association studies to identify susceptibility genes.

The first and key step in this endeavor is the creation of a high quality stroke biobank. During the two years of this project we will collect the biological samples and information from 800 individuals originating from 200 Portuguese multiplex families with ischemic stroke.

Research Project

Genetics of sporadic stroke (GENOPORT study)

Since the genetic basis of ischemic stroke may be different in families with a history of stroke (multiplex families) and in families without a history of stroke (sporadic cases), and sporadic cases are the most common, we propose to collect a second dataset of 500 sporadic stroke patients, 500 unaffected family members and 500 controls. This dataset will be used to test our findings in the familial dataset, to test findings from other research groups, and to test novel candidate genes for association.

Research Project

Stroke genomics (GENOSTROKE study)

The aim of this project is to identify genes whose expression pattern suggests their involvement in the pathogenesis of stroke, by comparing and contrasting the genetic profiles in affected individuals and controls with different ages-at-onset (age at the first stroke event) or ages-at-examination. We will use the microarray technology, a powerful technique which uses the information generated by the Human Genome Project and allows the quantitative exploration of genetic profiles at the entire genome level, and therefore becomes a discovery tool of new genes and pathways related to a great variety of conditions.

The genes that are differentially expressed in this study and that map to linkage regions identified on the STROKENETICS dataset will be further investigated for their association with stroke in our complete dataset. The field of stroke genetics needs the unified, comprehensive, multidisciplinary and unbiased approach proposed here. The recent development of new genetic, molecular, statistical and bioinformatics tools make this project both timely and essential. Stroke is the most preventable neurological disease and the identification of its genetic factors will have an important impact in the public health by increasing the motivation to implement preventive lifestyle changes in individuals at risk, which will ultimately result in a decrease of the number of strokes. The identification and characterization of stroke genes will also provide biological and clinical information on the development, prevention and treatment of strokes.

Funding

POCI 2010 (010.6/A019/2005)
GENOSTROKE: Stroke genomics.

Marie Curie International Reintegration Grant N. 513760
Stroke genetics

Collaborators

Hospital Egas Moniz
Miguel Viana-Baptista

Hospital Espírito Santo (Évora)
Isabel Henriques
Rita Lopes da Silva

Hospital Geral de Santo António (Porto)
Manuel Correia
Assunção Tuna
Gabriela Lopes

Hospital São Pedro (Vila Real)
Mário Rui Silva
João Paulo Gabriel

Hospital São Marcos (Braga)
João Ramalho Fontes
Carla Ferreira

Hospital Fernando Fonseca (Amadora Sintra)
Ana Amélia Pinto
Rita Moiron Silva

Hospital Distrital de Mirandela
Ilda Matos

Hospital de Santa Maria
José Ferro
Liliana Gouveia

Publications

Oliveira, S.A., Li, Y.J., Noureddine, M.A., Züchner, S., Qin, X.J., Pericak-Vance, M.A., Vance, J.M. (2005). Identification of risk and age-at-onset genes on chromosome 1p in Parkinson disease. American Journal of Human Genetics 77 :252-64

Noureddine, M.A., Qin, X.J., Oliveira, S.A., Skelly, T.J., van der Walt, J., Hauser, M.A., Pericak-Vance, M.A., Vance, J.M., Li, Y.J. (2005). Association between the neuron-specific RNA-binding protein ELAVL4 and Parkinson disease. Human Genetics 117 :27-33

Züchner, S., Noureddine, M., Kennerson, M., Verhoeven, K., Claeys, K., de Jonghe, P., Merory, J., Oliveira, S.A., Speer, M.C., Stenger, J.E., Walizada, G., Zhu, D., Pericak-Vance, M.A., Nicholson, G., Timmerman, V., Vance, J.M. (2005). Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nature Genetics 37 :289-294

Oliveira, S.A., Scott, W.K., Zhang, F., Stajich, J.M., Fujiwara, K., Hauser, M., Scott, B.L., Pericak-Vance, M.A., Vance, J.M., Martin, E.R. (2004). Linkage disequilibrium and haplotype tagging polymorphisms in the Tau H1 haplotype. Neurogenetics 5 :147-155

Li, Y.-J., Oliveira, S.A., Xu, P., Martin, E.R., Stenger, J.E., Scherzer, C.R., Hauser, M.A., Scott, W.K., Small, G.W., Nance, M.A., Watts, R.L., Hubble, J.P., Koller, W.C., Pahwa, R., Stern, M.B., Hiner, B.C., Jankovic, J., Goetz, C.G., Mastaglia, F., Middleton, L.T., Roses, A.D., Saunders, A.M., Schmechel, D.E., Gullans, S.R., Haines, J.L., Gilbert, J.R., Vance, J.M., Pericak-Vance, M.A. (2003). Glutathione S-Transferase omega 1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Hum. Mol. Gen. 12 :3259-3267

Oliveira, S.A., Scott, W.K., Martin, E.R., Pericak-Vance, M.A., Vance, J.M. (2003). Reply to Frequency of Parkin mutations in late-onset Parkinson disease Ann. Neurol. 54 :416-417

Oliveira, S.A., Scott, W.K., Nance, M.A., Watts, R.L., Hubble, J.P., Koller, W.C., Lyons, K.E., Pahwa, R., Stern, M.B., Hiner, B.C., Jankovic, J., Ondo, W.G., Allen Jr., F., Scott, B.L., Goetz, C.G., Small, G.W., Mastaglia, F.L., Stajich, J.M., Zhang, F., Booze, M.W., Reaves, J.A., Middleton, L.T., Haines, J.L., Pericak-Vance, M.A., Vance, J.M., Martin, E.R. (2003). Association study of Parkin gene polymorphisms with idiopathic Parkinson disease. Arch. Neurol. 60 :975-980

Oliveira, S.A., Martin, E.R., Scott, W.K., Nicodemus, K.K., Small, G.W., Schmechel, D.E., Doraiswamy, P.M., Roses, A.D., Saunders, A.M., Gilbert, J.R., Haines, J.L., Vance, J.M., Pericak-Vance, M.A. (2003). The Q7R Saitohin gene polymorphism is not associated with Alzheimer disease Neurosc. Lett. 347 :143-146

Oliveira, S.A., Scott, W.K., Martin, E.R., Nance, M.A., Watts, R.L., Hubble, J.P., Koller, W.C., Pahwa, R., Stern, M.B., Hiner, B.C., Ondo, W.G., Allen Jr., F.H., Scott, B.L., Goetz, C.G., Small, G.W., Mastaglia, F., Staijich, J.M., Zhang, F., Booze, M.W., Winn, M.P., Middleton, L.T., Haines, J.L., Pericak-Vance, M.A., Vance, J.M. (2003). Parkin mutations and susceptibility alleles in late-onset Parkinson disease. Ann. Neurol. 53 :624-629

Oliveira, S.A., Park, S.H., Lee, P., Bendelac, A., Shenk, T.E. (2002). Murine cytomegalovirus m02 gene family protects against natural killer cell-mediated immune surveillance. J. Virol. 76 :885-894

Oliveira, S.A., Scott, W.K., Pericak-Vance, M.A., Vance, J.M. (2001). Dissecting a complex disease using modern techniques of molecular biology Lab. Med. 32 :594-598

Oliveira, S.A., Shenk, T.E. (2001). Murine cytomegalovirus M78 protein, a G protein-coupled receptor homologue, is a constituent of the virion and facilitates accumulation of immediate-early viral mRNA Proc. Natl. Acad. Sci. 98 :3237-3242