We will study a relatively genetically homogeneous population to test the hypotheses that genetic factors are linked to schizophrenia. The study will focus on two populations. The first is from the Azores, a nine island archipelago in the Atlantic ocean that is a Portuguese state. The Azores have a centralized health system. All ten psychiatrists on the islands are collaborating with us on this project. The second population is from continental Portugal. The majority of the Azorean population is derived from this population base. Families with multiple affected members with schizophrenia, will be studied employing both parametric and non-parametric analytic strategies. We projected approximately 100 families segregating for schizophrenia, including over 300 affected family members. A complementary strategy will be used to study candidate loci. We will study a sample of 225 subjects suffering from schizophrenia and their parents (Total n=675) employing the haplotype relative risk and the transmission/disequilibrium test strategies. This strategy insures that we control for all ancestry for each subject, using the uninherited haplotype derived from the two parents. The third sample will include all other Azorean patients with schizophrenia, who agreed to participate in hopefully, achieving close to complete ascertainment of patients with schizophrenia in the Azores. This will be a valuable sample for linkage disequilibrium approaches given the nature of the Azorean population and provide us with a unique epidemiologic frame. These complementary strategies will allow us to cross validate any positive results. The careful diagnostic definition of phenotype will be based on detailed structured clinical data employing the Diagnostic Interview for Genetic Studies (DIGS), which we have translated into Portuguese. Our project is designed to capture a very complete history of the patients illness, as well as to be able to follow most subjects prospectively for a long period of time. This will be extremely valuable for achieving diagnostic certainty and minimizing false positives. An important new addition to this proposal is the Whitehead/MIT Center for Genome Research, that will perform a genome-wide scan and collaborate on all data analysis for the project.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Epidemiology and Genetics Review Committee (EPI)
Program Officer
Moldin, Steven Owen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University of New York at Buffalo
Schools of Medicine
United States
Zip Code
Franke, Barbara; Stein, Jason L; Ripke, Stephan et al. (2016) Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept. Nat Neurosci 19:420-431
Lee, S Hong; DeCandia, Teresa R; Ripke, Stephan et al. (2012) Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet 44:247-50
Fanous, Ayman H; Middleton, Frank A; Gentile, Karen et al. (2012) Genetic overlap of schizophrenia and bipolar disorder in a high-density linkage survey in the Portuguese Island population. Am J Med Genet B Neuropsychiatr Genet 159B:383-91
Machado-Vieira, Rodrigo; Pivovarova, Natalia B; Stanika, Ruslan I et al. (2011) The Bcl-2 gene polymorphism rs956572AA increases inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticulum calcium release in subjects with bipolar disorder. Biol Psychiatry 69:344-52
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011) Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43:969-76
Petryshen, T L; Middleton, F A; Kirby, A et al. (2005) Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Mol Psychiatry 10:366-74, 328
Middleton, Frank A; Pato, Carlos N; Gentile, Karen L et al. (2005) Gene expression analysis of peripheral blood leukocytes from discordant sib-pairs with schizophrenia and bipolar disorder reveals points of convergence between genetic and functional genomic approaches. Am J Med Genet B Neuropsychiatr Genet 136B:12-25
Pato, Carlos N; Middleton, Frank A; Gentile, Karen L et al. (2005) Genetic linkage of bipolar disorder to chromosome 6q22 is a consistent finding in Portuguese subpopulations and may generalize to broader populations. Am J Med Genet B Neuropsychiatr Genet 134B:119-21
Petryshen, T L; Middleton, F A; Tahl, A R et al. (2005) Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia. Mol Psychiatry 10:1074-88, 1057
Middleton, F A; Pato, M T; Gentile, K L et al. (2004) Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22. Am J Hum Genet 74:886-97

Showing the most recent 10 out of 16 publications