Genome-wide scan in Portuguese Island families identifies 5q31–5q35 as a susceptibility locus for schizophrenia and psychosis

Sklar, Pamela; Pato, Michele T.; Kirby, Andrew; Petryshen, Tracey L.; Medeiros, Helena; Carvalho, Célia Barreto; Macedo, A.; Dourado, Ana; Coelho, Isabel; Valente, J.; Soares, M.J.; Ferreira, Carlos Paz; Ma, Liang; Verner, Andrei; Hudson, Thomas J.; Morley, Christopher P.; Kennedy, James L.; Azevedo, Maria Helena Pinto de; Lander, Eric S.; Daly, Mark J.; Pato, Carlos N.

doi:10.1038/sj.mp.4001418

Cited by 108 publications

(95 citation statements)

References 34 publications

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“…FGF1 maps to 5q31 and FGFR1 maps to 8p11 and, again, both regions have been reported as linkage regions for schizophrenia. [49][50][51] Overall, this circumstantial evidence and the suggestive association we observed for both genes hints at the FGF signaling pathway being involved in schizophrenia.…”

Section: Discussionsupporting

confidence: 63%

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

et al. 2007

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Several lines of evidence, including expression analyses, brain imaging and genetic studies suggest that the integrity of myelin is disturbed in schizophrenia patients. In this study, we first reconstructed a pathway of 138 myelin-related genes, all involved in myelin structure, composition, development or maintenance. Then we performed a two-stage association analysis on these 138 genes using 771 single nucleotide polymorphisms (SNPs). Analysis of our data from 310 cases vs 880 controls demonstrated association of 10 SNPs from six genes. Specifically, we observed highly significant P-values for association in PIK4CA (observed P = 6.1 Â 10 À6 ). These findings remained significant after Bonferroni correction for 771 tests. The PIK4CA gene is located in the chromosome 22q11 deletion syndrome region, which is of particular interest because it has been implicated in schizophrenia. We also report weak association of SNPs in PIK3C2G, FGF1, FGFR1, ARHGEF10 and PSAP (observed Pp0.01). Our approach-of screening genes involved in a particular pathway for association-resulted in identification of several, mostly novel, genes associated with the risk of developing schizophrenia in the Dutch population.

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Section: Discussionsupporting

confidence: 63%

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

et al. 2007

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“…38 Subsequently, we reported linkage to an overlapping region at chromosome 5q31.1-q35.1 in a genome-wide scan of schizophrenia and schizoaffective depressed type (SA-D) families of Portuguese descent. 32 The maximum linkage signal in 29 families was an NPL ¼ 3.09 (P ¼ 0.0012) at marker D5S820, falling just short of genome-wide significance based on simulations of the data. 32 Higher density mapping in an expanded sample of 40 pedigrees produced a peak NPL ¼ 3.28 (P ¼ 0.00066) in the same region.…”

Section: Introductionmentioning

confidence: 90%

“…32 The maximum linkage signal in 29 families was an NPL ¼ 3.09 (P ¼ 0.0012) at marker D5S820, falling just short of genome-wide significance based on simulations of the data. 32 Higher density mapping in an expanded sample of 40 pedigrees produced a peak NPL ¼ 3.28 (P ¼ 0.00066) in the same region. Nominally significant linkage was obtained across a B35 cM region from D5S816 to D5S1456 located from 135.3 to 169 Mb.…”

Section: Introductionmentioning

confidence: 90%

“…32 Unrelated patients and control individuals were also ascertained from the Azorean immigrant population of Fall River, USA, and were confirmed to have all four grandparents from the Azores, Madeira, or continental Portugal. Controls consisted of unrelated individuals ascertained through a brochure left in community facilities (eg churches, community centers, doctor's offices, large employers) and four unaffected individuals that married into our linkage pedigrees.…”

Section: Subjectsmentioning

confidence: 99%

“…Controls consisted of unrelated individuals ascertained through a brochure left in community facilities (eg churches, community centers, doctor's offices, large employers) and four unaffected individuals that married into our linkage pedigrees. 32 Best estimate diagnoses of schizophrenia or SA-D according to DSM-IV criteria were made by two blinded researchers after review of clinical information, Diagnostic Interview for Genetic Studies (DIGS), 71 Operational Criteria Checklist for Psychotic Illness (OPCRIT), 72 and written narratives. The study received approval by all appropriate Institutional Review Boards and subjects provided informed consent.…”

Section: Subjectsmentioning

confidence: 99%

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Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia

et al. 2005

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We previously performed a genome-wide linkage scan in Portuguese schizophrenia families that identified a risk locus on chromosome 5q31-q35. This finding was supported by metaanalysis of 20 other schizophrenia genome-wide scans that identified 5q23.2-q34 as the second most compelling susceptibility locus in the genome. In the present report, we took a two-stage candidate gene association approach to investigate a group of gamma-aminobutyric acid (GABA) A receptor subunit genes (GABRA1, GABRA6, GABRB2, GABRG2, and GABRP) within our linkage peak. These genes are plausible candidates based on prior evidence for GABA system involvement in schizophrenia. In the first stage, associations were detected in a Portuguese patient sample with single nucleotide polymorphisms (SNPs) and haplotypes in GABRA1 (P ¼ 0.00062-0.048), GABRP (P ¼ 0.0024-0.042), and GABRA6 (P ¼ 0.0065-0.0088). The GABRA1 and GABRP findings were replicated in the second stage in an independent German family-based sample (P ¼ 0.0015-0.043). Supportive evidence for association was also obtained for a previously reported GABRB2 risk haplotype. Exploratory analyses of the effects of associated GABRA1 haplotypes on transcript levels found altered expression of GABRA6 and coexpressed genes of GABRA1 and GABRB2. Comparison of transcript levels in schizophrenia patients and unaffected siblings found lower patient expression of GABRA6 and coexpressed genes of GABRA1. Interestingly, the GABRA1 coexpressed genes include synaptic and vesicle-associated genes previously found altered in schizophrenia prefrontal cortex. Taken together, these results support the involvement of the chromosome 5q GABA A receptor gene cluster in schizophrenia, and suggest that schizophrenia-associated haplotypes may alter expression of GABA-related genes.

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Family-Based Association Study of Lithium-Related and Other Candidate Genes in Bipolar Disorder

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Purcell

Fagerness

et al. 2008

Arch Gen Psychiatry

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Genome-wide scan in Portuguese Island families identifies 5q31–5q35 as a susceptibility locus for schizophrenia and psychosis

Cited by 108 publications

References 34 publications

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia

Family-Based Association Study of Lithium-Related and Other Candidate Genes in Bipolar Disorder

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