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author:("tiselius, L")
1.  A genome wide linkage analysis in Swedish families with hereditary non‐familial adenomatous polyposis/non‐hereditary non‐polyposis colorectal cancer 
Gut  2006;55(3):362-366.
Background and aim
Known colorectal cancer syndromes, such as familial adenomatous polyposis and hereditary non‐polyposis colorectal cancer, have been identified in only a small proportion of cases with a family history of disease. In an attempt to identify loci harbouring novel predisposing genes, we have performed a genome wide linkage analysis in 18 colorectal cancer families recruited from the Department of Clinical Genetics at Karolinska Hospital, Sweden.
Multipoint parametric and non‐parametric linkage analyses were performed using two affected status criteria, stringent and less stringent. Parametric analysis was performed under the assumption of locus homogeneity and locus heterogeneity.
The initial scan performed using the less stringent affected status criteria revealed regions of interest on chromosome 11 (marker D11S1314: heterogeneity logarithm of odds (HLOD) score 1.96, non‐parametric LOD (NPL) score 1.28; and marker D11S908: HLOD score 2.10, NPL score 2.16) and chromosome 14 (marker D14S258: HLOD score 2.61, NPL score 2.88). Using the stringent affected status criteria, a locus on chromosome 22 was suggested in the parametric analysis (marker D22S315: HLOD score 1.26). After finemapping of the regions on chromosomes 11 and 14, HLOD and NPL scores were reduced but still within the range of suggestive linkage. Haplotype analysis revealed overlapping regions between D11S987 and D11S4207 (proximal region), D11S4120 and D11S4090 (distal region), on chromosome 11, and between D14S1038 and D14S1069 on chromosome 14.
Our study provides evidence of genetic heterogeneity among Swedish colorectal cancer families. Three novel regions were suggested to be of interest in a proportion of families analysed. Further studies are needed to confirm this result.
PMCID: PMC1856098  PMID: 16150854
linkage analysis; hereditary non‐polyposis colorectal cancer; familial adenomatous polyposis; colorectal cancer; chromosome 11; chromosome 14; chromosome 22
2.  Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32–31.1 
The best known hereditary colorectal cancer syndromes, familial adenomatous polyposis (FAP) and hereditary non‐polyposis colorectal cancer (HNPCC), constitute about 2% of all colorectal cancers, and there are at least as many non‐FAP, non‐HNPCC cases where the family history suggests a dominantly inherited colorectal cancer risk. Recently, a locus on chromosome 9q22.2–31.2 was identified by linkage analysis in sib pairs with colorectal cancer or adenoma.
Linkage analysis for the suggested locus on chromosome 9 was carried out in an extended Swedish family. This family had previously been investigated but following the identification of adenomas in several previously unaffected family members, these subjects were now considered to be gene carriers.
In the present study, we found linkage of adenoma and colorectal cancer to chromosome 9q22.32–31.1 with a multipoint LOD score of 2.4. We were also able to define the region for this locus to 7.9 cM between the markers D9S280 and D9S277.
Our result supports the presence of a susceptibility locus predisposing to adenoma and colorectal cancer in this chromosomal region.
PMCID: PMC2564647  PMID: 16467217
adenoma; chromosome 9; colorectal cancer; linkage analysis
3.  Genetic epidemiology of glioma 
British Journal of Cancer  2001;84(3):429-434.
The present study performed a segregation analysis of a cohort of first-degree relatives (FDR) of glioma patients. The families with two or more gliomas were also expanded to determine if any more gliomas could be detected, and if any other types of cancers were associated. These glioma-prone families (n = 24/432) were extended to include first-, second- and third-degree relatives (n = 807) and a cohort was assembled, the standardized incidence risk for other types of cancer calculated and the pedigrees investigated for a possible mode of inheritance. A segregation analysis of the 2141 FDR in 297 families, performed using the Pointer software, did not clearly reject a multifactorial model χ2 (3) = 6.13,P< 0.2. However, when letting all parameters be free, the recessive model provided the best fit. In the extended families, no increased risk of other types of cancer was found. This population-based study proposes that familial glioma occurs in about 5% of all glioma cases and that 1% have a possible autosomal dominant inheritance. This first segregation analysis performed in familial glioma must be cautiously interpreted, but an autosomal recessive gene provided the best fit, which could possibly explain 2% of all glioma cases. © 2001 Cancer Research Campaign
PMCID: PMC2363745  PMID: 11161412
familial; glioma; astrocytoma; segregation analyses; hereditary; autosomal recessive
4.  Segregation analysis of epithelial ovarian cancer in Finland. 
British Journal of Cancer  1998;77(9):1537-1541.
Epithelial ovarian cancer is known to aggregate in families. The dominantly inherited ovarian cancer predisposing genes, BRCA1, BRCA2 and genes involved in the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, have recently been identified. However, in the majority of families with more than one case of ovarian cancer, dominant inheritance cannot be recognized. We investigated familial clustering of epithelial ovarian cancer in a population-based sample of 663 Finnish ovarian cancer patients. A segregation analysis with the POINTER software was conducted on the 937 nuclear families from these 663 pedigrees. The major gene model was favoured, and the sporadic and multifactorial models were strongly rejected. In the studied population, the best fitting model was a recessive mode of inheritance, and 8% of ovarian cancer patients were estimated to be homozygous for the deleterious genotype. This evidence for recessively inherited ovarian cancer predisposition should be interpreted cautiously, as the analysis is subject to certain errors, which are discussed in the article. Results of this analysis, however, strongly emphasize the role of genetic factors in all familial aggregation of epithelial ovarian cancer.
PMCID: PMC2150198  PMID: 9652774
5.  Indices and graphical approaches for the detection of interindividual and interethnic variations in codeine metabolism 
Aims To evaluate the use of different graphical methods and statistical tests in the detection of interindividual and interethnic variations in codeine metabolism. Various urinary metabolic ratios (MR) for codeine O-demethylation were also compared for their ability to determine phenotype.
Methods Frequency histograms, normal test variable (NTV) plots and admixture analysis were used to examine the distributions of the urinary MRs for codeine O-demethylation, N-demethylation and glucuronidation in 132 Caucasian and 222 Chinese subjects.
Results In the Caucasian population, apparent bimodality was shown in both a frequency histogram and NTV plot of the log MR of codeine O-demethylation (codeine/(morphine (M)+M-3 and M-6-glucuronide (M3G and M6G)+ normorphine (NM)). Admixture analysis confirmed the co-segregation of codeine O-demethylation and debrisoquine hydroxylation. The antimode for the codeine O-demethylation MR between extensive and poor metabolisers was located between 5.5 and 8.3. A simplified MR for codeine O-demethylation (codeine/M3G) demonstrated a similar correlation with the debrisoquine MR to the more complex MR, allowing a simplification of the analytical method for phenotyping. The Chinese population had significantly higher median MRs for codeine N-demethylation, O-demethylation and glucuronidation, which was shown clearly in the frequency histograms, but not in the NTV plots.
Conclusion A histogram seems preferable over a NTV plot for assigning phenotype using the codeine O-demethylation MR, because it is clear and simple. Interethnic difference in the metabolism of codeine are also better visualised from the histograms.
PMCID: PMC2042844  PMID: 9296317
codeine metabolism; polymorphism; debrisoquine; metabolic ratio; ethnic groups; Caucasian; Chinese; graphical methods; admixture analysis
6.  Cluster headache is an autosomal dominantly inherited disorder in some families: a complex segregation analysis. 
Journal of Medical Genetics  1995;32(12):954-956.
We investigated the mode of inheritance of cluster headache in 370 families. The probands were from a neurological clinic in Jutland and two departments of neurology in Copenhagen County, Denmark. The criteria of the International Headache Society were used. The patterns of segregation of cluster headache were assessed by complex segregation analysis performed with the computer program POINTER. Of the 370 probands with cluster headache, 25 had 36 relatives with cluster headache. The segregation analysis suggests that cluster headache has an autosomal dominant gene (p < 0.10) with a penetrance of 0.30-0.34 in males and 0.17-0.21 in females. The gene is present in 3 to 4% of males and 7 to 10% of females with cluster headache. An autosomal dominant gene has a role in cluster headache in some families.
PMCID: PMC1051776  PMID: 8825923
7.  Investigation of inheritance of chronic inflammatory bowel diseases by complex segregation analysis. 
BMJ : British Medical Journal  1993;306(6869):20-24.
OBJECTIVE--To investigate the mode of inheritance of ulcerative colitis and Crohn's disease by complex segregation analysis. DESIGN--Cross sectional population based survey of familial occurrence of chronic inflammatory bowel disease. SETTING--Population of the Copenhagen county in 1987. SUBJECTS--662 patients in whom inflammatory bowel disease had been diagnosed before 1979, of whom 637 (96%) provided adequate information. Of 504 patients with ulcerative colitis, 54 had 77 relatives with ulcerative colitis and of 133 patients with Crohn's disease, five had seven relatives with Crohn's disease. MAIN OUTCOME MEASURES--Patterns of segregation of either disease as assessed by complex segregation analysis performed with the computer program POINTER. RESULTS--The analysis suggested that a major dominant gene with a penetrance of 0.20-0.26 is present in 9-13% of adult patients with ulcerative colitis. The analysis did not allow for other components in the familial aggregation. For Crohn's disease the best fitting model included a major recessive gene with complete penetrance, for which 7% of the patients are homozygous. However, this model was not significantly different from a multifactorial model. CONCLUSIONS--The segregation pattern indicates that a major dominant gene has a role in ulcerative colitis, and suggests that a major recessive gene has a role in Crohn's disease.
PMCID: PMC1676367  PMID: 8435571
8.  Von Hippel-Lindau disease: a genetic study. 
Journal of Medical Genetics  1991;28(7):443-447.
Genetic aspects of von Hippel-Lindau (VHL) disease were studied in familial and isolated cases. Complex segregation analysis with pointers was performed in 38 kindreds with two or more affected members. Dominant inheritance with almost complete penetrance in the highest age classes (0.96 at 51 to 60 and 0.99 at 61 to 70 years) was confirmed and there was no evidence of heterogeneity between families ascertained through complete and incomplete selection. The point prevalence of heterozygotes in East Anglia was 1.89/100,000 (1/53,000) persons with an estimated birth incidence of 2.73/100,000 (1/36,000) live births. Reproductive fitness was 0.83. Direct and indirect estimates of the mutation rate were 4.4 (95% CI 0.9 to 7.9) x 10(-6)/gene/generation and 2.32 x 10(-6)/gene/generation respectively. There was no significant association between parental age or birth order and new mutations for VHL disease.
PMCID: PMC1016952  PMID: 1895313
9.  A linkage study of a large pedigree with X linked centronuclear myopathy. 
Journal of Medical Genetics  1990;27(5):281-283.
Centronuclear myopathy (CNM) is a muscle wasting disorder that occurs in three distinct forms. Previous studies have shown linkage between the X linked form of the disease and the Xq28 probes ST14, DX13, and F8C. Our study on a previously unreported, three generation, X linked CNM family confirms linkage between these markers and the CNM locus (Z = 3.21, theta = 00). However, results from the laboratory of J-L Mandel (Samson and Hanover, personal communication) on a number of X linked CNM families exclude genetic linkage from the region Xq26-qter, suggesting genetic heterogeneity in this condition.
PMCID: PMC1017075  PMID: 2352255
10.  Genetics of plasma paroxonase activity 
Journal of Medical Genetics  1982;19(6):424-426.
Complex segregation analysis of plasma paroxonase activity gives evidence for a major locus with incomplete dominance (d = 0·70) causing high activity plus a background of multifactorial inheritance (heritability = 0·09).
PMCID: PMC1048954  PMID: 6296391

Results 1-10 (10)