Genetic dissection of multigenic disorders, such as schizophrenia, is truly challenging yet possible, particularly with the availability of the human genome sequence. Genomewide linkage scans in schizophrenia have suggested that susceptibility loci may be present on several chromosomes. It is possible that in founder populations there will be fewer susceptibility loci and alleles. In addition, founder populations often exhibit less environmental heterogeneity than do other populations and allow detailed genealogical research and reconstruction of extended multigenerational pedigrees. Availability of such large pedigrees should facilitate the detection of linkage. We have collected a large number of families with schizophrenia from the genetically isolated population of the Afrikaners from South Africa. We performed a 10-cM genomewide scan on 143 small families, 34 of which were informative for linkage. Using both nonparametric and parametric linkage analyses, we obtained evidence for a small number of disease loci on chromosomes 1, 9, and 13. The locus on chromosome 1 reached genomewide significance levels and represents a novel susceptibility locus for schizophrenia. In addition to providing evidence for linkage for chromosome 1, we also identified a proband with a uniparental disomy (UPD) of the entire chromosome 1. This is the first time a UPD has been described in a patient with schizophrenia, lending further support to involvement of chromosome 1 in schizophrenia susceptibility in the Afrikaners. We propose to fine-map the chromosome 1p locus identified through the 10-cM genomewide scan of the Afrikaner family samples using microsatellite markers for a 1-cM coverage and SNPs for a denser coverage. We also propose to use genotypic information from the proband with the UPD to identify and define an Afrikaner risk haplotype on chromosome 1. In addition, we propose to perform a 10-cM genomewide scan in a second set of multiply affected Afrikaner families that we have collected to identify additional loci or strengthen the evidence and narrow the regions of involvement for already implicated loci. Finally, we propose to collect neurocognitive data from multiply affected Afrikaner families to use as quantitative endophenotypes of schizophrenia in a QTL linkage analysis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH061399-07
Application #
7154115
Study Section
Genome Study Section (GNM)
Program Officer
Lehner, Thomas
Project Start
2000-08-01
Project End
2010-04-09
Budget Start
2007-12-01
Budget End
2010-04-09
Support Year
7
Fiscal Year
2008
Total Cost
$456,338
Indirect Cost
Name
Columbia University (N.Y.)
Department
Psychiatry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Takata, Atsushi; Ionita-Laza, Iuliana; Gogos, Joseph A et al. (2016) De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. Neuron 89:940-7
Rodriguez-Murillo, Laura; Xu, Bin; Roos, J Louw et al. (2014) Fine mapping on chromosome 13q32-34 and brain expression analysis implicates MYO16 in schizophrenia. Neuropsychopharmacology 39:934-43
Ionita-Laza, Iuliana; Xu, Bin; Makarov, Vlad et al. (2014) Scan statistic-based analysis of exome sequencing data identifies FAN1 at 15q13.3 as a susceptibility gene for schizophrenia and autism. Proc Natl Acad Sci U S A 111:343-8
Takata, Atsushi; Xu, Bin; Ionita-Laza, Iuliana et al. (2014) Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron 82:773-80
Huey, Edward D; Nagy, Peter L; Rodriguez-Murillo, Laura et al. (2013) C9ORF72 repeat expansions not detected in a group of patients with schizophrenia. Neurobiol Aging 34:1309.e9-10
Gilman, Sarah R; Chang, Jonathan; Xu, Bin et al. (2012) Diverse types of genetic variation converge on functional gene networks involved in schizophrenia. Nat Neurosci 15:1723-8
Xu, Bin; Ionita-Laza, Iuliana; Roos, J Louw et al. (2012) De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet 44:1365-9
Malhotra, Dheeraj; McCarthy, Shane; Michaelson, Jacob J et al. (2011) High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72:951-63
Xu, Bin; Roos, J Louw; Dexheimer, Phillip et al. (2011) Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat Genet 43:864-8
Vacic, Vladimir; McCarthy, Shane; Malhotra, Dheeraj et al. (2011) Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 471:499-503

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