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- Christensen, G Bryce, et al.
(författare)
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Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses.
- 2010
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 70, s. 735-744
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS: We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS: Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. CONCLUSIONS: Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate (c) 2010 Wiley-Liss, Inc.
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- Forabosco, P., et al.
(författare)
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Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus
- 2006
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 7:7, s. 609-614
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Tidskriftsartikel (refereegranskat)abstract
- A genetic contribution to the development of systemic lupus erythematosus (SLE) is well established. Several genome-wide linkage scans have identified a number of putative susceptibility loci for SLE, some of which have been replicated in independent samples. This study aimed to identify the regions showing the most consistent evidence for linkage by applying the genome scan meta-analysis (GSMA) method. The study identified two genome-wide suggestive regions on 6p21.1-q15 and 20p11-q13.13 (P-value=0.0056 and P-value=0.0044, respectively) and a region with P-value<0.01 on 16p13-q12.2.The region on chromosome 6 contains the human leukocyte antigen cluster, and the chromosome 16 and 20 regions have been replicated in several cohorts. The potential importance of the identified genomic regions are also highlighted. These results, in conjunction with data emerging from dense single nucleotide polymorphism typing of specific regions or future genome-wide association studies will help guide efforts to identify the actual predisposing genetic variation contributing to this complex genetic disease.
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- Johanneson, Bo, 1964-
(författare)
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Genetic Mapping of Susceptibility Genes for Systemic Lupus Erythematosus
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) is a complex autoimmune disease with unknown etiology. The aim of this thesis was to identify susceptibility regions through genetic mapping, using model-based linkage analysis on nuclear and extended SLE multicase families.In the first paper we performed a genome scan on 19 genetically homogenous Icelandic and Swedish families. One region at 2q37 was identified with a significant linkage with contribution from both populations (Z=4.24). Five other regions 2q11, 4p13, 9p22, 9p13 and 9q13 showed suggestive linkage (Z>2.0).In the second paper, 87 families from 10 different countries were analysed only for chromosome 1. One region at 1q31 showed significant linkage (Z=3.79) with contribution from families from all populations, including Mexicans and Europeans. Four other regions 1p36, 1p21, 1q23, and 1q25, showed levels of suggestive linkage. Linkage for most regions was highly dependent on what population was used, which indicated strong genetic heterogeneity in the genetic susceptibility for SLE.In the two last papers, we used the positional candidate gene strategy, in order to investigate candidate genes in two regions linked to SLE. For the Bcl-2 gene (at 18q21) we could not detect any association with SLE using three different markers. However, when we investigated the tightly linked low-affinity family of FcγR genes (at 1q23), we could find association for two risk alleles in the FcγRIIA and FcγRIIIA genes. The risk alleles were transmitted to SLE patients on one specific haplotype and therefore are not independent risk alleles.The results show that model-based linkage analysis is a strong approach in the search for susceptibility genes behind complex diseases like SLE.
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- Johanneson, Bo, et al.
(författare)
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Systematic validation of hypothesis-driven candidate genes for cervical cancer in a genome-wide association study
- 2014
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 35:9, s. 2084-2088
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Tidskriftsartikel (refereegranskat)abstract
- A large number of genetic associations with cervical cancer have been reported in hypothesis-driven candidate gene studies, but most studies have not included an independent replication or the results have been inconsistent between studies. In order to independently validate these associations, we re-examined 58 candidate gene/regions previously reported to be associated with cervical cancer using the gene-based Adaptive Rank Truncated Product (ARTP) test in a genome-wide association study of 1,034 cervical cancer patients and 3,948 controls from the Swedish population. Of the 58 gene/regions, 8 had a nominal p-value < 0.05 (Tumor necrosis factor [TNF], p = 5.0×10(-4); DEAD (Asp-Glu-Ala-Asp) box helicase 1 [DDX1], p = 2.2×10(-3); Exonuclease 1 [EXO1], p=4.7×10(-3); Excision repair cross-complementing rodent repair deficiency, complementation group 1 [ERCC1], p = 0.020; Transmembrane channel-like 6 and 8 genes [TMC6-TMC8], p = 0.023; Secreted phosphoprotein 1 [SPP1], p= 0.028; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 [ERBB2], p = 0.033 and Chloride channel, voltage-sensitive 7 [CLCN7], p = 0.047). After correction for multiple testing only TNF remained statistically significant (p = 0.028). Two single-nucleotide polymorphisms that are in nearly perfect linkage disequilibrium (LD) (rs2857602 and rs2844484) contributed most to the association with TNF. However, they are not independent from the previously reported associations within the MHC region. The very low number of previously reported associations with cervical cancer that replicate in the Swedish population underscore the need to apply more stringent criteria when reporting associations, including the prerequisite of replicating the association as part of the original study.
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- Lu, Lingyi, et al.
(författare)
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Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG
- 2012
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 72:4, s. 410-426
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD?=?1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members. METHODS. In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups. RESULTS. Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD cores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology. CONCLUSIONS. These results will be useful in prioritizing future susceptibility gene discovery efforts in thiscommon cancer. Prostate 72: 410-426, 2012. (C) 2011 Wiley Periodicals, Inc.
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