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E Cummings,
G Donohoe,
A Hargreaves,
S Moore,
C Fahey,
T G Dinan,
C McDonald,
E O'Callaghan,
F A O'Neill,
J L Waddington,
K C Murphy, D W Morris,
M Gill,
A Corvin
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: The Schizophrenia Psychiatric Genome-wide Association (GWAS) Consortium recently reported on five novel schizophrenia susceptibility loci. The most significant finding mapped to a micro-RNA, MIR-137, which may be involved in regulating the function of other schizophrenia and bipolar disorder susceptibility genes. METHOD: We genotyped 821 patients with confirmed DSM-IV diagnoses of schizophrenia, bipolar affective disorder I and schizoaffective disorder for the risk SNP (rs1625579) and investigated the clinical profiles of risk allele carriers using a within-case design. We also assessed neurocognitive performance in a subset of cases (n=399) and controls (n=171). RESULTS: Carriers of the risk allele had lower scores for an OPCRIT-derived positive symptom factor (p=0.04) and lower scores on a lifetime measure of psychosis incongruity (p=0.017). Risk allele carriers also had more cognitive deficits involving episodic memory and attentional control. CONCLUSION: This is the first evidence that the MIR-137 risk variant may be associated with a specific subgroup of psychosis patients. Although the effect of this single SNP was not clinically relevant, investigation of the impact of carrying multiple risk SNPs in the MIR-137 regulatory network on diagnosis and illness profile may be warranted.
Neuroscience Letters 09/2012; · 2.11 Impact Factor
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[show abstract]
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ABSTRACT: Suicide is the leading cause of death in schizophrenia. An association between suicidal behavior and both higher and lower cognitive ability in schizophrenia has been reported. To clarify this relationship, we investigated whether the relationship between suicidality and neurocognition varied according to differences in suicidal ideation and behavior.
Three hundred and ten patients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder were categorized based on patient and staff interviews as either non-suicide attempters, non-attempters expressing suicidal ideation, single suicide attempters, or multiple suicide attempters. These groups were compared on a neuropsychological battery examining current general cognitive ability, episodic and working memory, and attentional control.
Neuropsychological performance in those with a history of suicidal ideation (n=63), and those who had made one suicide attempt (n=48) was comparable. Together, these groups outperformed patients with no history of either suicidal behavior or ideation (n=172) on measures of IQ, episodic memory and working memory. Only differences in global cognition remained significant after controlling for between-group differences in depressive symptoms. Those who had either expressed suicidal ideation and/or made a single suicide attempt demonstrated trend level advantages in neuropsychological tests over those that had made multiple suicide attempts.
These findings support earlier evidence of an association between suicidality and neurocognitive ability in schizophrenia. Specifically, these data suggest that patients who have contemplated suicide or made a single suicide attempt have better cognitive functioning than those who have not. Suicidality in multiple attempters, who do not perform better in neurocognitive tests than those who have neither contemplated nor attempted suicide, is likely to be influenced by factors other than neurocognitive ability.
Biological Psychiatry 07/2012; 140(1-3):232-6. · 8.28 Impact Factor
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X Chen,
G Lee,
B S Maher,
A H Fanous,
J Chen,
Z Zhao,
A Guo,
E van den Oord,
P F Sullivan,
J Shi, [......],
A McQuillin,
J Pimm,
C Hultman,
P Lichtenstein,
P Sklar,
S M Purcell,
E Scolnick,
D St Clair,
D H R Blackwood,
K S Kendler
[show abstract]
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ABSTRACT: We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.
Molecular psychiatry 11/2011; 16(11):1117-29. · 15.05 Impact Factor
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A Jablensky,
D Angelicheva,
G J Donohoe,
M Cruickshank,
D N Azmanov, D W Morris,
A McRae,
C S Weickert,
K W Carter,
D Chandler, [......],
M Cooper,
M Phillips,
J Badcock,
E Bramon-Bosch,
O P Almeida,
L Flicker,
M Gill,
A Corvin,
S Macgregor,
L Kalaydjieva
[show abstract]
[hide abstract]
ABSTRACT: In a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 Mb interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated with CD scores and memory performance. The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins. The two tagging SNPs with strongest evidence of association were located around the overlapping putative promoters, with rs2224391 predicted to alter a transcription factor binding site (TFBS). Sequencing the promoter region identified 22 SNPs, many predicted to affect TFBSs, in a tight linkage disequilibrium block. Luciferase reporter assays confirmed promoter activity in the predicted promoter region, and demonstrated marked downregulation of expression in the LYRM4 direction under the haplotype comprising the minor alleles of promoter SNPs, which however is not driven by rs2224391. Experimental evidence from LYRM4 expression in lymphoblasts, gel-shift assays and modelling of DNA breathing dynamics pointed to two adjacent promoter SNPs, rs7752203-rs4141761, as the functional variants affecting expression. Their C-G alleles were associated with higher transcriptional activity and preferential binding of nuclear proteins, whereas the G-A combination had opposite effects and was associated with poor memory and high CD scores. LYRM4 is a eukaryote-specific component of the mitochondrial biogenesis of Fe-S clusters, essential cofactors in multiple processes, including oxidative phosphorylation. LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis.Molecular Psychiatry advance online publication, 4 October 2011; doi:10.1038/mp.2011.129.
Molecular psychiatry 10/2011; · 15.05 Impact Factor
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Molecular psychiatry 08/2011; 17(2):118-9. · 15.05 Impact Factor
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G Spalletta, D W Morris,
F Angelucci,
I A Rubino,
I Spoletini,
P Bria,
G Martinotti,
A Siracusano,
G Bonaviri,
S Bernardini,
C Caltagirone,
P Bossù,
G Donohoe,
M Gill,
A P Corvin
[show abstract]
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ABSTRACT: Brain-derived neurotrophic factor (BDNF) gene variants may potentially influence behaviour. In order to test this hypothesis, we investigated the relationship between BDNF Val66Met polymorphism and aggressive behaviour in a population of schizophrenic patients. Our results showed that increased number of BDNF Met alleles was associated with increased aggressive behaviour.
European Psychiatry 10/2010; 25(6):311-3. · 2.77 Impact Factor
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E Cummings,
G Donohoe,
C McDonald,
T G Dinan,
F A O'Neill,
E O'Callaghan,
J L Waddington,
K C Murphy,
M Gill, D W Morris,
A Corvin
Biological Psychiatry 09/2010; 122(1-3):273-5. · 8.28 Impact Factor
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H J Williams,
N Norton,
S Dwyer,
V Moskvina,
I Nikolov,
L Carroll,
L Georgieva,
N M Williams, D W Morris,
E M Quinn, [......],
P Sklar,
S Purcell,
V L Nimgaonkar,
G Kirov,
P Holmans,
A Corvin,
D Rujescu,
N Craddock,
M J Owen,
M C O'Donovan
[show abstract]
[hide abstract]
ABSTRACT: A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 × 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 × 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N=18 945, schizophrenia plus bipolar disorder N=21 274 and controls N=38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 × 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 × 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.
Molecular psychiatry 04/2010; 16(4):429-41. · 15.05 Impact Factor
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L S Carroll,
N M Williams,
V Moskvina,
E Russell,
N Norton,
H J Williams,
T Peirce,
L Georgieva,
S Dwyer,
D Grozeva, [......],
A Corvin,
M Gill,
D Rujescu,
P Sham,
P Holmans,
I Jones,
G Kirov,
N Craddock,
M C O'Donovan,
M J Owen
[show abstract]
[hide abstract]
ABSTRACT: We earlier reported a genome-wide significant linkage to schizophrenia at chromosome 17 that was identified in a single pedigree (C702) consisting of six affected, male siblings with DSM-IV schizophrenia and prominent mood symptoms. In this study, we adopted several approaches in an attempt to map the putative disease locus. First, mapping the source of linkage to chromosome 17 in pedigree C702. We refined the linkage region in family C702 to a 21-marker segment spanning 11.7 Mb at 17q23-q24 by genotyping a total of 50 microsatellites across chromosome 17 in the pedigree. Analysis of data from 1028 single nucleotide polymorphisms (SNPs) across the refined linkage region identified a single region of homozygosity present in pedigree C702 but not in 2938 UK controls. This spanned ~432 kb of the gene encoding protein kinase C, alpha (PRKCA), the encoded protein of which has been implicated in the pathogenesis of psychiatric disorders. Analysis of pedigree C702 by oligonucleotide-array comparative genome hybridization excluded the possibility that this region of homozygosity was because of a deletion. Mutation screening of PRKCA identified a rare, four-marker haplotype (C-HAP) in the 3' untranslated region of the gene, which was present in the homozygous state in all six affected members of pedigree C702. No other homozygotes were observed in genotype data for a total of 6597 unrelated Europeans (case N=1755, control N=3580 and parents of probands N=1262). Second, association analysis of C702 alleles at PRKCA. The low-frequency haplotype (C-HAP) showed a trend for association in a study of unrelated schizophrenia cases and controls from the UK (661 cases, 2824 controls, P=0.078 and odd ratio (OR)=1.9) and significant evidence for association when the sample was expanded to include cases with bipolar (N=710) and schizoaffective disorder (N=50) (psychosis sample: 1421 cases, 2824 controls, P=0.037 and OR=1.9). Given that all the affected members of C702 are male, we also undertook sex-specific analyses. This revealed that the association was strongest in males for both schizophrenia (446 male cases, 1421 male controls, P=0.008 and OR=3.9) and in the broader psychosis group (730 male cases, 1421 male controls, P=0.008 and OR=3.6). Analysis of C-HAP in follow-up samples from Ireland and Bulgaria revealed no evidence for association in either the whole sample or in males alone, and meta-analysis of all male psychosis samples yielded no significant evidence of association (969 male cases, 1939 male controls, 311 male probands P=0.304 and OR=1.4). Third, association mapping of the pedigree C702 linkage region. Independent of pedigree C702, genotype data from the Affymetrix 500k GeneChip set were available for 476 patients with schizophrenia and 2938 controls from the United Kingdom. SNPs in PRKCA showed evidence for association with schizophrenia that achieved gene-wide significance (P=0.027). Moreover, the same SNP was the most significantly associated marker out of the 1028 SNPs genotyped across the linkage region (rs873417, allelic P=0.0004). Follow-up genotyping in samples from Ireland, Bulgaria and Germany did not show consistent replication, but meta-analysis of all samples (4116 cases and 6491 controls) remained nominally significant (meta-analysis P=0.026, OR=1.1). We conclude that, although we have obtained convergent lines of evidence implicating both rare and common schizophrenia risk variants at PRKCA, none of these is individually compelling. However, the evidence across all approaches suggests that further study of this locus is warranted.
Molecular psychiatry 09/2009; 15(11):1101-11. · 15.05 Impact Factor
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M C O'Donovan,
N Norton,
H Williams,
T Peirce,
V Moskvina,
I Nikolov,
M Hamshere,
L Carroll,
L Georgieva,
S Dwyer, [......],
S Cichon,
M M N|[ouml]|then,
M Gill,
A P Corvin,
D Rujescu,
P V Gejman,
G Kirov,
N Craddock,
N M Williams,
M J Owen
[show abstract]
[hide abstract]
ABSTRACT: We and others have previously reported linkage to schizophrenia on chromosome 10q25–q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 single-nucleotide polymorphisms (SNPs) mapping to 10q25–q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with P<0.01 (n=40) were genotyped in an additional 163 UK cases and those markers that remained nominally significant at P<0.01 (n=22) were genotyped in replication samples from Ireland, Germany and Bulgaria consisting of a total of 1664 cases with schizophrenia and 3541 controls. Only one SNP, rs17101921, was nominally significant after meta-analyses across the replication samples and this was genotyped in an additional six samples from the United States/Australia, Germany, China, Japan, Israel and Sweden (n=5142 cases/6561 controls). Across all replication samples, the allele at rs17101921 that was associated in the GWAS showed evidence for association independent of the original data (OR 1.17 (95% CI 1.06–1.29), P=0.0009). The SNP maps 85 kb from the nearest gene encoding fibroblast growth factor receptor 2 (FGFR2) making this a potential susceptibility gene for schizophrenia.Keywords: FGFR2, schizophrenia, genome-wide association study
Molecular Psychiatry 09/2008; 14(1):30-36. · 13.67 Impact Factor
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M C O'Donovan,
N Norton,
H Williams,
T Peirce,
V Moskvina,
I Nikolov,
M Hamshere,
L Carroll,
L Georgieva,
S Dwyer, [......],
S Cichon,
M M Nöthen,
M Gill,
A P Corvin,
D Rujescu,
P V Gejman,
G Kirov,
N Craddock,
N M Williams,
M J Owen
[show abstract]
[hide abstract]
ABSTRACT: We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 single-nucleotide polymorphisms (SNPs) mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with P<0.01 (n=40) were genotyped in an additional 163 UK cases and those markers that remained nominally significant at P<0.01 (n=22) were genotyped in replication samples from Ireland, Germany and Bulgaria consisting of a total of 1664 cases with schizophrenia and 3541 controls. Only one SNP, rs17101921, was nominally significant after meta-analyses across the replication samples and this was genotyped in an additional six samples from the United States/Australia, Germany, China, Japan, Israel and Sweden (n=5142 cases/6561 controls). Across all replication samples, the allele at rs17101921 that was associated in the GWAS showed evidence for association independent of the original data (OR 1.17 (95% CI 1.06-1.29), P=0.0009). The SNP maps 85 kb from the nearest gene encoding fibroblast growth factor receptor 2 (FGFR2) making this a potential susceptibility gene for schizophrenia.
Molecular psychiatry 09/2008; 14(1):30-6. · 15.05 Impact Factor
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M. A. R. Ferreira,
M. C. O'Donovan,
Y. A. Meng,
I. R. Jones,
D. M. Ruderfer,
L. Jones,
J. Fan,
G. Kirov,
R. H. Perlis,
E. K. Green, [......],
M. J. Daly,
A. P. Corvin,
P. A. Holmans,
D. H. Blackwood,
H. M. Gurling,
M. J. Owen,
S. M. Purcell,
P. Sklar,
N. Craddock,
Consor Wellcome Trust Case Control
[show abstract]
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ABSTRACT: {To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336
Nature Genetics. 01/2008; 40(9):1056-1058.
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A Corvin,
K A McGhee,
K Murphy,
G Donohoe,
J M Nangle,
S Schwaiger,
N Kenny,
S Clarke,
D Meagher,
J Quinn,
P Scully,
P Baldwin,
D Browne,
C Walsh,
J L Waddington, D W Morris,
M Gill
[show abstract]
[hide abstract]
ABSTRACT: The D-amino acid oxidase (DAO) signaling pathway has been implicated in schizophrenia pathogenesis. This may be mediated through modulation of NMDA function by DAO, which is in turn activated by DAO activator (DAOA, formerly G72). Chumakov et al. (2002); PNAS 99: 13675-13680, identifying the novel schizophrenia susceptibility gene DAOA/G30 and a number of independent studies have since reported evidence of association between the DAOA and DAO genes and schizophrenia. However, at least two studies have failed to replicate the epistatic interaction between these loci described in the original report and there have been differences in the associated alleles/haplotypes reported at each locus. In this study, we performed association and epistasis analyses of the DAOA/G30 and DAO loci in a sample of 373 cases with DSM-IV schizophrenia/schizoaffective disorder and 812 controls from the Republic of Ireland. Corrected for the number of tests performed, we found evidence for association between markers at both genes and schizophrenia: DAOA/G30 (P = 0.005, OR = 1.34 (1.09, 1.65)) and DAO (P = 0.003, OR = 1.43 (1.12, 1.84). The data suggest that evidence for association at DAO (marker rs2111902) is more consistent than previously realized, particularly in Caucasian schizophrenia populations. We identified evidence for epistatic interaction between the associated SNPs at DAOA and DAO genes in contributing to schizophrenia risk (OR = 9.3 (1.4, 60.5). Based on these data, more systematic investigation of genes involved in DAO signaling is required.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 11/2007; 144B(7):949-53. · 3.70 Impact Factor
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Molecular Psychiatry 10/2007; 12(9):795-6. · 13.67 Impact Factor
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[show abstract]
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ABSTRACT: Molecular genetic studies have suggested a reading disability (RD, dyslexia) susceptibility locus on chromosome 15q. We have previously mapped this locus by association to the region surrounding D15S994. Very little is known about the neurobiological processes involved in RD, and therefore selecting positional candidate genes for analysis based upon function is difficult. Nevertheless we were able to identify two functional candidates based upon existing hypotheses. Both were phospholipase genes, phospholipase C beta 2 (PLCB2) and phospholipase A2, group IVB (cytosolic; PLA2G4B). D15S944 is located within PLCB2 and is 1.6 Mb from PLA2G4B. We examined each gene for association using a mixed direct and indirect association approach, a case (n = 164)/control (n = 174) sample, and a partially overlapping sample of 178 RD parent-proband trios from South Wales and England. Mutation analysis revealed 14 sequence variants in PLCB2 and 33 variants in PLA2G4B. All non-synonymous SNPs were genotyped as were SNPs across each gene with maximum distance between SNPs of 6 kb. Case-control analyses revealed modest evidence (0.01 < P < 0.05) for association between a single variant in PLCB2 and two variants in PLA2G4B. However, association was not confirmed in the family based sample. As the latter sample has previously generated replicated significant evidence for association between RD and markers/haplotypes surrounding D15S944, it should have sufficient power to detect association to variants in susceptibility gene itself. We conclude that neither gene accounts for the association signal we previously observed. As these are the only clear cut functional candidate genes in the region, identification of the putative susceptibility locus for RD on 15q will require more methodical non-hypothesis driven positional cloning approaches.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2004; 129B(1):97-103. · 3.70 Impact Factor
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N M Williams,
A Preece, D W Morris,
G Spurlock,
N J Bray,
M Stephens,
N Norton,
H Williams,
M Clement,
S Dwyer,
C Curran,
J Wilkinson,
V Moskvina,
J L Waddington,
M Gill,
A P Corvin,
S Zammit,
G Kirov,
M J Owen,
M C O'Donovan
[show abstract]
[hide abstract]
ABSTRACT: Recent research suggests that variation in the gene encoding dystrobrevin binding protein (DTNBP1) confers susceptibility to schizophrenia. Thus far, no specific risk haplotype has been identified in more than 1 study.
To confirm DTNBP1 as a schizophrenia susceptibility gene, to identify and replicate specific risk and protective haplotypes, and to explore relationships between DTNBP1 and the phenotype.
Genetic association study based on mutation detection and case-control analysis.
All subjects were unrelated and ascertained from general (secondary care) psychiatric inpatient and outpatient services.
The Cardiff, Wales, sample included 708 white subjects from the United Kingdom and Ireland (221 females) who met DSM-IV criteria for schizophrenia and were individually matched for age, sex, and ethnicity to 711 blood donor controls (233 females). Mean +/- SD age at first psychiatric contact for cases was 23.6 +/- 7.7 years; mean age at ascertainment was 41.8 +/- 13.5 years. The Dublin, Ireland, sample included 219 white subjects from the Republic of Ireland who met DSM-III-R criteria for schizophrenia or schizoaffective disorder and 231 controls. The mean age of the Irish cases was 46.0 +/- 8.5 years; mean age at first psychiatric contact was 25.2 +/- 12.4 years.
Evidence for association between the DTNBP1 locus and schizophrenia.
In the Cardiff sample, there was no evidence for association with previously implicated haplotypes but strong evidence for association with multiple novel haplotypes. Maximum evidence was found for a novel 3-marker haplotype (global P<.001), composed of 1 risk haplotype (P =.01) and 2 protective haplotypes, 1 common (P =.006) and 1 rare (P<.001). Specific risk and protective haplotypes were replicated in the Dublin sample (P =.02,.047, and.006, respectively). The only phenotypic variable associated with any haplotype was between the common protective haplotype and higher educational achievement (P =.02, corrected for multiple tests).
DTNBP1 is a susceptibility gene for schizophrenia. Specific risk and protective haplotypes were identified and replicated. Association with educational achievement may suggest protection mediated by IQ, although this needs to be confirmed in an independent data set.
Archives of General Psychiatry 04/2004; 61(4):336-44. · 12.02 Impact Factor
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M E Talkowski,
K V Chowdari,
S Deshpande,
B K Thelma,
N Williams,
M J Owen,
M C O'Donavan,
K M Prasad,
J A Wood, D W Morris,
M Gill,
Quirino Cordeiro,
Homero Vallada,
V L Nimgaonkar
Biological Psychiatry 04/2004; 55(8):748. · 8.28 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Two recent association studies have implicated the neuregulin-1 gene (NRG1) at chromosome 8p21-22 as a susceptibility gene for schizophrenia. Stefansson et al identified three 'at-risk' haplotypes (HapA, B and C) which spanned the NRG1 locus and shared a common core haplotype. Subsequently, they demonstrated evidence that the core haplotype was associated with schizophrenia in an independent Scottish sample. To confirm and refine this haplotype we investigated the NRG1 locus in an independent Irish case-control sample. We did not find the core haplotype to be associated in our sample. However, we identified a refined 2-marker haplotype (HapB(IRE)) that shared common alleles with one of the Icelandic 'at-risk' haplotypes and is in significant excess in the Irish cases (19.4%) vs controls (12.3%) (P=0.013). This refined 'at-risk' haplotype is also in significant excess in the Scottish case sample (17.0% vs 13.5%; P=0.036). Interestingly, this refined 'at-risk' haplotype is positioned close to an EST cluster of unknown function (Hs.97362) within intron 1 of NRG1.
Molecular Psychiatry 03/2004; 9(2):208-13. · 13.67 Impact Factor
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D Turic,
L Robinson,
M Duke, D W Morris,
V Webb,
M Hamshere,
C Milham,
E Hopkin,
K Pound,
S Fernando, [......],
M Easton,
N Williams,
M Van Den Bree,
R Chowdhury,
J Gruen,
J Stevenson,
M Krawczak,
M J Owen,
M C O'Donovan,
J Williams
[show abstract]
[hide abstract]
ABSTRACT: Linkage disequilibrium (LD) mapping was used to follow up reports of linkage between reading disability (RD) and an 18 cM region of chromosome 6p21.3-22. Using a two-stage approach, we tested for association between RD and 22 microsatellite markers in two independent samples of 101 (Stage 1) and 77 (Stage 2) parent/proband trios in which RD was rigorously defined. The most significant replicated associations were observed between combinations of markers D6S109/422/1665 (Stage 1, P=0.002 (adjusted for multiple testing); Stage 2, P=0.0001) and D6S506/1029/1660 (Stage 1, P=0.02 (adjusted), Stage 2, P=0.0001). The only two-marker association observed in both samples was with D6S422/1665 (P=0.01, 0.04). No single marker showed replicated association but D6S506 produced values of P=0.01 and 0.08 which were significant when combined (P=0.02). We observed weaker and less consistent evidence of association in a region of confirmed linkage to RD in previous studies. The most consistently significant haplotypic association D6S109/422/1665, showed association with single-word reading, spelling, phonological awareness, phonological decoding, orthographic accuracy and random automised naming, but not with vocabulary or Attention Deficit Hyperactivity Disorder. Our findings strongly support the presence of a gene contributing to RD in a region of chromosome 6 between markers D6S109 and D6S1260, but do not rule out the presence of a gene between D6S1556 and MOG.
Molecular Psychiatry 03/2003; 8(2):176-85. · 13.67 Impact Factor
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D W Morris,
L Robinson,
D Turic,
M Duke,
V Webb,
C Milham,
E Hopkin,
K Pound,
S Fernando,
M Easton,
M Hamshere,
N Williams,
P McGuffin,
J Stevenson,
M Krawczak,
M J Owen,
M C O'Donovan,
J Williams
[show abstract]
[hide abstract]
ABSTRACT: Family-based association mapping was used to follow up reports of linkage between reading disability (RD) and a genomic region on chromosome 15q. Using a two-stage approach, we ascertained 101 (stage 1) and 77 (stage 2) parent-proband trios, in which RD was characterized rigorously. In stage 1, a set of eight microsatellite markers spanning the region of putative linkage was used and a highly significant association was detected between RD and a three-marker haplotype (D15S994/D15S214/D15S146: P and empirical P < 0.001). A significant association with the same three-marker haplotype was also observed in the second-stage sample (P = 0.009, empirical P = 0.006). Our data therefore provide strong evidence for one or more genes contributing to RD being located in the vicinity of the region including D15S146 and D15S994. In addition, our results provide support for association analysis being a useful method to map susceptibility loci for complex disorders.
Human Molecular Genetics 03/2000; 9(5):843-8. · 7.64 Impact Factor
