Browsing by Author "Middleton, Frank A."
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- Common polygenic variation contributes to risk of schizophrenia and bipolardisorderPublication . Purcell, S. M.; Wray, N. R.; Stone, J. L.; Visscher, P. M.; O'Donovan, M. C.; Sullivan, P. F.; Sklar, P.; Leader, S. M.; Ruderfer, D. M.; McQuillin, A.; Morris, D. W.; O'Dushlaine, C. T.; Corvin, A.; Holmans, P. A.; Macgregor, S.; Gurling, H.; Blackwood, D. H.; Craddock, N. J.; Gill, M.; Hultman, C. M.; Kirov, G. K.; Lichtenstein, P.; Muir, W. J.; Owen, M. J.; Pato, Carlos N.; Scolnick, E. M.; St Clair, D.; Williams, N. M.; Georgieva, L.; Nikolov, I.; Norton, N.; Williams, H.; Toncheva, D.; Milanova, V.; Helander, E. F.; Kenny, E.; Quinn, E. M.; Choudhury, K.; Datta, S.; Pimm, J.; Thirumalai, S.; Puri, V.; Krasucki, R.; Lawrence, J.; Quested, D.; Bass, N.; Crombie, C.; Fraser, G.; Leh, K. S.; Walker, N.; Black-wood, D. H.; McGhee, K. A.; Pickard, B.; Malloy, P.; Maclean, A. W.; Van Beck, M.; Pato, Michele T.; Medeiros, Helena; Middleton, Frank A.; Carvalho, Célia; Morley, C.; Fanous, Ayman H.; Conti, D.; Knowles, James A.; Ferreira, Carlos Paz; Macedo, António; Kirby, A. N.; Ferreira, M. A.; Daly, M. J.; Cham-bert, K.; Kuruvilla, F.; Gabriel, S. B.; Ardlie, K.; Moran, J. L.Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
- Genetic Overlap of Schizophrenia and Bipolar Disorder in a High-Density Linkage Survey inthe Portuguese Island PopulationPublication . Fanous, Ayman H.; Middleton, Frank A.; Gentile, Karen; Amdur, Richard L.; Maher, Brion S.; Zhao, Zhongming; Sun, Jingchun; Medeiros, Helena; Carvalho, Célia; Ferreira, Susana R.; Macedo, António; Knowles, James A.; Azevedo, Maria H.; Pato, Michele T.; Pato, Carlos N.Recent family and genome-wide association studies strongly suggest shared genetic risk factors for schizophrenia (SZ) and bipolar disorder (BP). However, linkage studies have not been used to test for statistically significant genome-wide overlap between them. Forty-seven Portuguese families with sibpairs concordant for SZ, BP, or psychosis (PSY, which includes either SZ or psychotic BP) were genotyped for over 57,000 markers using the Affymetrix 50K Xba SNP array. NPL and Kong and Cox LOD scores were calculated in Merlin for all three phenotypes. Empirical significance was determined using 1,000 gene-dropping simulations. Significance of genome-wide genetic overlap between SZ and BP was determined by the number of simulated BP scans having the same number of loci jointly linked with the real SZ scan, and vice versa. For all three phenotypes, a number of regions previously linked in this sample remained so. For BP, chromosome 1p36 achieved significance (11.54-15.71 MB, LOD = 3.51), whereas it was not even suggestively linked at lower marker densities, as did chromosome 11q14.1 (89.32-90.15 MB, NPL = 4.15). Four chromosomes had loci at which both SZ and BP had NPL ≥ 1.98, which was more than would be expected by chance (empirical P = 0.01 using simulated SZ scans; 0.07 using simulated BP scans), although they did not necessarily meet criteria for suggestive linkage individually. These results suggest that high-density marker maps may provide greater power and precision in linkage studies than lower density maps. They also further support the hypothesis that SZ and BP share at least some risk alleles.
- 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 6q22Publication . Middleton, Frank A.; Pato, Michele T.; Gentile, Karen; Morley, C. P.; Zhao, X.; Eisener, A. F.; Brown, A.; Petryshen, T. L.; Kirby, A. N.; Medeiros, Helena; Carvalho, Célia; Macedo, António; Dourado, A.; Coelho, I.; Valente, J.; Soares, M. J.; Ferreira, Carlos Paz; Lei, M.; Azevedo, Maria H.; Kennedy, J. L.; Daly, M. J.; Sklar, P.; Pato, Carlos N.We performed a linkage analysis on 25 extended multiplex Portuguese families segregating for bipolar disorder, by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the GeneChip Human Mapping 10K Array (HMA10K). Of these families, 12 were used for a direct comparison of the HMA10K with the traditional 10-cM microsatellite marker set and the more dense 4-cM marker set. This comparative analysis indicated the presence of significant linkage peaks in the SNP assay in chromosomal regions characterized by poor coverage and low information content on the microsatellite assays. The HMA10K provided consistently high information and enhanced coverage throughout these regions. Across the entire genome, the HMA10K had an average information content of 0.842 with 0.21-Mb intermarker spacing. In the 12-family set, the HMA10K-based analysis detected two chromosomal regions with genomewide significant linkage on chromosomes 6q22 and 11p11; both regions had failed to meet this strict threshold with the microsatellite assays. The full 25-family collection further strengthened the findings on chromosome 6q22, achieving genomewide significance with a maximum nonparametric linkage (NPL) score of 4.20 and a maximum LOD score of 3.56 at position 125.8 Mb. In addition to this highly significant finding, several other regions of suggestive linkage have also been identified in the 25-family data set, including two regions on chromosome 2 (57 Mb, NPL = 2.98; 145 Mb, NPL = 3.09), as well as regions on chromosomes 4 (91 Mb, NPL = 2.97), 16 (20 Mb, NPL = 2.89), and 20 (60 Mb, NPL = 2.99). We conclude that at least some of the linkage peaks we have identified may have been largely undetected in previous whole-genome scans for bipolar disorder because of insufficient coverage or information content, particularly on chromosomes 6q22 and 11p11.
- Rare chromosomal deletions and duplications increase risk of schizophreniaPublication . Craddock, N. J.; Gill, M.; Hultman, C. M.; Lichtenstein, P.; McQuillin, A.; Pato, Carlos N.; Ruderfer, D. M.; Owen, M. J.; St Clair, David; Sullivan, P. F.; Sklar, P.; Purcell, S. M.; Stone, J. L; Korn, Joshua; Macgregor, S.; Morris, D. W.; O'Dushlaine, C. T.; Daly, M. J.; Visscher, P. M.; Holmans, P. A.; Scolnick, E: M.; Williams, N. M.; Georgieva, L.; Nikolov, I.; Norton, N.; Williams, H.; Toncheva, D.; Milanova, V.; Thelander, Emma F.; Sullivan, P. F.; Kenny, E.; Waddington, John L.; Choudhury, K.; Datta, S.; Pimm, J.; Thirumalai, S.; Puri, V.; Krasucki, R.; Lawrence, J.; Quested, D.; Bass, N.; Curtis, David; Gurling, H.; Crombie, C.; Fraser, G.; Kwan, Soh Leh; Walker, N.; Muir, W. J.; McGhee, K. A.; Pickard, B.; Malloy, P.; Maclean, A. W.; Van Beck, Margaret; Visscher, P. M.; Pato, Michele T.; Medeiros, Helena; Middleton, Frank A.; Carvalho, Célia; Morley, C.; Fanous, Ayman H.; Conti, D.; Knowles, James A.; Ferreira, Carlos Paz; Macedo, António; Azevedo, Maria H.; McCarroll, Steve A.; Daly, M. J.; Chambert, Kimberly; Gates, CaseySchizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73–90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia and also in neurodevelopmental disorders, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients (12). Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.