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1.
Lange EM Robbins CM Gillanders EM Zheng SL Xu J Wang Y White KA Chang BL Ho LA Trent JM Carpten JD Isaacs WB Cooney KA 《Human genetics》2007,121(1):49-55
Prostate cancer linkage studies have suggested the existence of a prostate cancer susceptibility gene on chromosome 17q21–22.
We now report the results of an extended linkage analysis including 95 new multiplex prostate cancer families and 9 additional
microsatellite markers resulting in a maximum LOD score of 2.99 at approximately 81–82 cM for all 453 pedigrees. Results from
these 95 new pedigrees provide additional support for a chromosome 17q21–22 prostate cancer susceptibility gene. Inclusion
of the 9 additional markers significantly reduced the size of the candidate region, as defined using a 1-LOD support interval,
especially when focusing analyses on subsets of pedigrees with four or more confirmed affecteds or average age of diagnosis
less than or equal to 65 years. A novel subset analysis of only those families (n = 147) that had four or more prostate cancer cases and an average age of prostate cancer diagnosis ≤ 65 years results in
a maximum LOD score of 5.49 at 78 cM with a 1-LOD support interval of 10 cM. This large set of pedigrees with four more prostate
cancer cases characterized by early-onset disease will serve as a useful resource for identifying the putative 17q21–22 prostate
cancer susceptibility gene. 相似文献
2.
Lange EM Ho LA Beebe-Dimmer JL Wang Y Gillanders EM Trent JM Lange LA Wood DP Cooney KA 《Human genetics》2006,119(4):400-407
Epidemiological and twin studies have consistently demonstrated a strong genetic component to prostate cancer (PCa) susceptibility. To date, numerous linkage studies have been performed to identify chromosomal regions containing PCa susceptibility genes. Unfortunately, results from these studies have failed to form any obvious consensus regarding which regions are most likely to contain genes that may contribute to PCa predisposition. One plausible explanation for the difficulty in mapping susceptibility loci is the existence of considerable heterogeneity in the phenotype of PCa, with significant variation in clinical stage and grade of disease even among family members. To address this issue, we performed a genome-wide linkage scan on 71 informative families with two or more men with aggressive PCa. When only men with aggressive PCa were coded as affected, statistically significant evidence for linkage at chromosome 15q12 was detected (LOD=3.49; genome-wide p=0.005). Furthermore, the evidence for linkage increased when analyses were restricted to Caucasian–American pedigrees (n=65; LOD=4.05) and pedigrees with two confirmed aggressive cases (n=42, LOD=4.76). Interestingly, a 1-LOD support interval about our peak at 15q12 overlaps a region of suggestive linkage, 15q11, identified by a recent linkage study on 1,233 PCa families by the International Consortium for Prostate Cancer Genetics. Using a more rigid definition of PCa in linkage studies will result in a severe reduction in sample sizes available for study, but may ultimately prove to increase statistical power to detect susceptibility genes for this multigenic trait. 相似文献
3.
Schaid DJ Stanford JL McDonnell SK Suuriniemi M McIntosh L Karyadi DM Carlson EE Deutsch K Janer M Hood L Ostrander EA 《Human genetics》2007,121(6):729-735
Despite evidence that prostate cancer has a genetic etiology, it has been extremely difficult to confirm genetic linkage results
across studies, emphasizing the large extent of genetic heterogeneity associated with this disease. Because prostate cancer
is common—approximately one in six men will be diagnosed with prostate cancer in their life—genetic linkage studies are likely
plagued by phenocopies (i.e., men with prostate cancer due to environmental or lifestyle factors), weakly penetrant alleles,
or a combination of both, making it difficult to replicate linkage findings. One way to account for heterogeneous causes is
to use clinical information that is related to the aggressiveness of disease as an endpoint for linkage analyses. Gleason
grade is a measure of prostate tumor differentiation, with higher grades associated with more aggressive disease. This semi-quantitative
score has been used as a quantitative trait for linkage analysis in several prior studies. Our aim was to determine if prior
linkage reports of Gleason grade to specific loci could be replicated, and to ascertain if new regions of linkage could be
found. Gleason scores were available for 391 affected sib pairs from 183 hereditary prostate cancer pedigrees as part of the
PROGRESS study. Analyzing Gleason score as a quantitative trait, and using microsatellite markers, suggestive evidence for linkage
(P-value ≤ 0.001) was found on chromosomes 19q and 5q, with P-values ≤ 0.01 observed on chromosomes 3q, 7q, and 16q. Our results confirm reports of Gleason score linkage to chromosome
19q and suggest new loci for further investigation. 相似文献
4.
A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q 总被引:19,自引:0,他引:19
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Wiltshire S Hattersley AT Hitman GA Walker M Levy JC Sampson M O'Rahilly S Frayling TM Bell JI Lathrop GM Bennett A Dhillon R Fletcher C Groves CJ Jones E Prestwich P Simecek N Rao PV Wishart M Bottazzo GF Foxon R Howell S Smedley D Cardon LR Menzel S McCarthy MI 《American journal of human genetics》2001,69(3):553-569
Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest. 相似文献
5.
Assessment of the effect of age at onset on linkage to bipolar disorder: evidence on chromosomes 18p and 21q
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Lin PI McInnis MG Potash JB Willour VL Mackinnon DF Miao K Depaulo JR Zandi PP 《American journal of human genetics》2005,77(4):545-555
Previous evidence suggests that the inheritance of bipolar disorder (BP) may vary depending on the age at onset (AAO). Therefore, we sought to incorporate AAO as a covariate in linkage analyses of BP using two different methods, LODPAL and ordered-subset analysis (OSA), in genomewide scans of 150 multiplex pedigrees with 874 individuals. The LODPAL analysis identified two loci, on chromosomes 21q22.13 (LOD = 3.29; empirical chromosomewide P value = .009) and 18p11.2 (LOD = 2.83; empirical chromosomewide P = .05), with increased linkage among subjects who had early onset (AAO < or = 21 years) and later onset (AAO >21 years), respectively. The finding on 21q22.13 was significant at the chromosomewide level, even after correction for multiple testing. Moreover, a similar finding was observed in an independent sample of 65 pedigrees (LOD = 2.88; empirical chromosomewide P = .025). The finding on 18p11.2 was only nominally significant and was not observed in the independent sample. However, 18p11.2 emerged as one of the strongest regions in the OSA (LOD = 2.92; empirical P = .001), in which it was the only finding to meet chromosomewide levels of significance after correction for multiple testing. These results suggest that 21q22.13 and 18p11.2 may harbor genes that increase the risks for early-onset and later-onset forms of BP, respectively. There have been previous reports of linkage on 21q22.13 and 18p11.2, but the findings have not been consistent. This inconsistency may be due to differences in the AAO characteristics of the samples examined. Future studies to fine map susceptibility genes for BP on chromosomes 21q22.13 and 18p11.2 should take AAO into account. 相似文献
6.
Berry R Schroeder JJ French AJ McDonnell SK Peterson BJ Cunningham JM Thibodeau SN Schaid DJ 《American journal of human genetics》2000,67(1):82-91
Recent studies suggest that hereditary prostate cancer is a complex disease involving multiple susceptibility genes and variable phenotypic expression. While conducting a genomewide search on 162 North American families with > or =3 members affected with prostate cancer (PRCA), we found evidence for linkage to chromosome 20q13 with two-point parametric LOD scores >1 at multiple sites, with the highest two-point LOD score of 2.69 for marker D20S196. The maximum multipoint NPL score for the entire data set was 3.02 (P=.002) at D20S887. On the basis of findings from previous reports, families were stratified by the presence (n=116) or absence (n=46) of male-to-male transmission, average age of diagnosis (<66 years, n=73; > or =66 years, n=89), and number of affected individuals (<5, n=101; > or =5, n=61) for further analysis. The strongest evidence of linkage was evident with the pedigrees having <5 family members affected with prostate cancer (multipoint NPL 3.22, P=.00079), a later average age of diagnosis (multipoint NPL 3.40, P=.0006), and no male-to-male transmission (multipoint NPL 3.94, P=.00007). The group of patients having all three of these characteristics (n=19) had a multipoint NPL score of 3.69 (P=.0001). These results demonstrate evidence for a PRCA susceptibility locus in a subset of families that is distinct from the groups more likely to be linked to previously identified loci. 相似文献
7.
Genome-wide Study of Families with Absolute Pitch Reveals Linkage to 8q24.21 and Locus Heterogeneity
Elizabeth Theusch Analabha Basu Jane Gitschier 《American journal of human genetics》2009,85(1):112-119
Absolute pitch (AP) is the rare ability to instantaneously recognize and label tones with their musical note names without using a reference pitch for comparison. The etiology of AP is complex. Prior studies have implicated both genetic and environmental factors in its genesis, yet the molecular basis for AP remains unknown. To locate regions of the human genome that may harbor AP-predisposing genetic variants, we performed a genome-wide linkage study on 73 multiplex AP families by genotyping them with 6090 SNP markers. Nonparametric multipoint linkage analyses were conducted, and the strongest evidence for linkage was observed on chromosome 8q24.21 in the subset of 45 families with European ancestry (exponential LOD score = 3.464, empirical genome-wide p = 0.03). Other regions with suggestive LOD scores included chromosomes 7q22.3, 8q21.11, and 9p21.3. Of these four regions, only the 7q22.3 linkage peak was also evident when 19 families with East Asian ancestry were analyzed separately. Though only one of these regions has yet reached statistical significance individually, we detected a larger number of independent linkage peaks than expected by chance overall, indicating that AP is genetically heterogeneous. 相似文献
8.
Fine-mapping chromosome 20 in 230 systemic lupus erythematosus sib pair and multiplex families: evidence for genetic epistasis with chromosome 16q12
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Gaffney PM Langefeld CD Graham RR Ortmann WA Williams AH Rodine PR Moser KL Behrens TW 《American journal of human genetics》2006,78(5):747-758
The presence of systemic lupus erythematosus (SLE) susceptibility genes on chromosome 20 is suggested by the observation of genetic linkage in several independent SLE family collections. To further localize the genetic effects, we typed 59 microsatellites in the two best regions, as defined by genome screens. Genotypes were analyzed for statistical linkage and/or association with SLE, by use of a combination of nonparametric linkage methods, family-based tests of association (transmission/disequilibrium and pedigree disequilibrium tests), and haplotype-sharing statistics (haplotype runs test), in a set of 230 SLE pedigrees. Maximal evidence for linkage to SLE was to 20p12 (LOD = 2.84) and 20q13.1 (LOD = 1.64) in the white pedigrees. Subsetting families on the basis of evidence for linkage to 16q12 significantly improved the LOD scores at both chromosome 20 locations (20p12 LOD = 5.06 and 20q13 LOD = 3.65), consistent with epistasis. We then typed 162 single-nucleotide polymorphism markers across a 1.3-Mb candidate region on 20q13.1 and identified several SNPs that demonstrated significant evidence for association. These data provide additional support for linkage and association to 20p12 and 20q13.1 in SLE and further refine the intervals of interest. These data further suggest the possibility of epistatic relationships among loci within the 20q12, 20q13, and 16q12 regions in SLE families. 相似文献
9.
Analysis of the prostate cancer-susceptibility locus HPC20 in 172 families affected by prostate cancer
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Bock CH Cunningham JM McDonnell SK Schaid DJ Peterson BJ Pavlic RJ Schroeder JJ Klein J French AJ Marks A Thibodeau SN Lange EM Cooney KA 《American journal of human genetics》2001,68(3):795-801
A recent study of hereditary prostate cancer has provided evidence for a prostate cancer-susceptibility locus, HPC20, which maps to 20q13. To assess further the potential contribution of this locus to prostate cancer susceptibility, we studied 172 unrelated families affected by prostate cancer, using 17 polymorphic markers across a 98.5-cM segment of chromosome 20 that contains the candidate region. Parametric analysis, allowing for heterogeneity, resulted in an overall HLOD score of 0.09 (P=.39) at D20S171, under the assumption of linkage in 6% of families. Mode-of-inheritance-free analysis of the entire data set resulted in a maximal Zlr score of 0.76 (LOD 0.13; P=.22) at the same location. The strongest evidence for linkage was seen in the subset of 16 black families (LOD 0.86; Zlr=1.99; P=.023) between markers D20S893 and D20S120, near the putative location of HPC20. Although some positive results were observed, our linkage study does not provide statistically significant support for the existence of a prostate cancer-susceptibility locus HPC20 at 20q13. 相似文献
10.
Systemic lupus erythematosus susceptibility loci defined by genome scan meta-analysis 总被引:4,自引:0,他引:4
To date, several susceptibility loci for systemic lupus erythematosus (SLE) have been identified by individual genome-wide scans, but many of these loci have shown inconsistent results across studies. Additionally, many individual studies are at the lower limit of acceptable power recommended for declaring significant linkage. The genome search meta-analysis (GSMA) has been proposed as a valid and robust method for combining several genome scan results. The aim of this study is to investigate whether there is any consistent evidence of linkage across multiple studies, and to identify novel SLE susceptibility loci by using GSMA method. Twelve genome scan results generated from nine independent studies have been used for the present GSMA. All together, the data consists of 605 families with 1,355 SLE affected individuals from three self-reported ethnicities; Caucasian, African-American, and Hispanic. For each study, the genome was divided into 120 bins (30 cM) and ranked according to the maximum evidence of linkage within each bin. The ranks were summed and averaged across studies following which the significance was assessed by the permutation tests. The present study identified two genomic locations at 6p22.3–6p21.1 and 16p12.3–16q12.2 that met genome-wide significance (p<0.000417). The identified region at 6p22.3–6p21.1 contains the HLA region. The combined p-values using Fisher’s method also supported the significance in these regions. Clustering of significant adjacent bins was observed for chromosomes 6 and 16. Additionally, there are 12 other bins with two point-wise p-values (Psumrnk and Pord) <0.05, suggesting that these bin regions are highly likely to contain SLE susceptibility loci. Among them, present GSMA also identified two novel regions at 4q32.1–4q34.3 and 13q13.2–13q22.2. However, separate analysis using only Caucasian populations identified the strongest evidence for linkage at chromosome 6p21.1–6q15 (Psumrnk=0.00021). One interesting novel region suggests that 3q22.1–3q25.33 (Psumrnk=0.01376) may be an ethnicity-specific SLE linkage. In summary, the present GSMA have identified two statistically significant genomic regions that reconfirmed the SLE linkage at chromosomes 6 and 16. 相似文献
11.
Celedón JC Soto-Quiros ME Avila L Lake SL Liang C Fournier E Spesny M Hersh CP Sylvia JS Hudson TJ Verner A Klanderman BJ Freimer NB Silverman EK Weiss ST 《Human genetics》2007,120(5):691-699
Although asthma is a major public health problem in certain Hispanic subgroups in the United States and Latin America, only
one genome scan for asthma has included Hispanic individuals. Because of small sample size, that study had limited statistical
power to detect linkage to asthma and its intermediate phenotypes in Hispanic participants. To identify genomic regions that
contain susceptibility genes for asthma and airway responsiveness in an isolated Hispanic population living in the Central
Valley of Costa Rica, we conducted a genome-wide linkage analysis of asthma (n = 638) and airway responsiveness (n = 488) in members of eight large pedigrees of Costa Rican children with asthma. Nonparametric multipoint linkage analysis
of asthma was conducted by the NPL-PAIR allele-sharing statistic, and variance component models were used for the multipoint
linkage analysis of airway responsiveness as a quantitative phenotype. All linkage analyses were repeated after exclusion
of the phenotypic data of former and current smokers. Chromosome 12q showed some evidence of linkage to asthma, particularly
in nonsmokers (P < 0.01). Among nonsmokers, there was suggestive evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 2.33
at 146 cM). After genotyping 18 additional short-tandem repeat markers on chromosome 12q, there was significant evidence of
linkage to airway responsiveness on chromosome 12q24.31 (LOD = 3.79 at 144 cM), with a relatively narrow 1.5-LOD unit support
interval for the observed linkage peak (142–147 cM). Our results suggest that chromosome 12q24.31 contains a locus (or loci)
that influence a critical intermediate phenotype of asthma (airway responsiveness) in Costa Ricans.
This work was supported by grants HL04370 and HL66289 from the National Institutes of Health. 相似文献
12.
Genomewide Multipoint Linkage Analysis of Seven Extended Palauan Pedigrees with Schizophrenia, by a Markov-Chain Monte Carlo Method 总被引:2,自引:0,他引:2
Nicola J. Camp Susan L. Neuhausen Josepha Tiobech Anthony Polloi Hilary Coon Marina Myles-Worsley 《American journal of human genetics》2001,69(6):1278-1289
Palauans are an isolated population in Micronesia with lifetime prevalence of schizophrenia (SCZD) of 2%, compared to the world rate of approximately 1%. The possible enrichment for SCZD genes, in conjunction with the potential for reduced etiological heterogeneity and the opportunity to ascertain statistically powerful extended pedigrees, makes Palauans a population of choice for the mapping of SCZD genes. We have used a Markov-chain Monte Carlo method to perform a genomewide multipoint analysis in seven extended pedigrees from Palau. Robust multipoint parametric and nonparametric linkage (NPL) analyses were performed under three nested diagnostic classifications-core, spectrum, and broad. We observed four regions of interest across the genome. Two of these regions-on chromosomes 2p13-14 (for which, under core diagnostic classification, NPL=6.5 and parametric LOD=4.8) and 13q12-22 (for which, under broad diagnostic classification, parametric LOD=3.6, and, under spectrum diagnostic classification, parametric LOD=3.5)-had evidence for linkage with genomewide significance, after correction for multiple testing; with the current pedigree resource and genotyping, these regions are estimated to be 4.3 cM and 19.75 cM in size, respectively. A third region, with intermediate evidence for linkage, was identified on chromosome 5q22-qter (for which, under broad diagnostic classification, parametric LOD=2.5). The fourth region of interest had only borderline suggestive evidence for linkage (on 3q24-28; for this region, under broad diagnostic classification, parametric LOD=2.0). All regions exhibited evidence for genetic heterogeneity. Our findings provide significant evidence for susceptibility loci on chromosomes 2p13-14 and 13q12-22 and support both a model of genetic heterogeneity and the utility of a broader set of diagnostic classifications in the population from Palau. 相似文献
13.
Comparison of microsatellites versus single-nucleotide polymorphisms in a genome linkage screen for prostate cancer-susceptibility Loci
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Schaid DJ Guenther JC Christensen GB Hebbring S Rosenow C Hilker CA McDonnell SK Cunningham JM Slager SL Blute ML Thibodeau SN 《American journal of human genetics》2004,75(6):948-965
Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a 2-3-fold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Although the suggestion of linkage has been reported for many chromosomes, the most promising regions have been difficult to replicate. In this study, we compare genome linkage scans using microsatellites with those using single-nucleotide polymorphisms (SNPs), performed in 467 men with prostate cancer from 167 families. For the microsatellites, the ABI Prism Linkage Mapping Set version 2, with 402 microsatellite markers, was used, and, for the SNPs, the Early Access Affymetrix Mapping 10K array was used. Our results show that the presence of linkage disequilibrium (LD) among SNPs can lead to inflated LOD scores, and this seems to be an artifact due to the assumption of linkage equilibrium that is required by the current genetic-linkage software. After excluding SNPs with high LD, we found a number of new LOD-score peaks with values of at least 2.0 that were not found by the microsatellite markers: chromosome 8, with a maximum model-free LOD score of 2.2; chromosome 2, with a LOD score of 2.1; chromosome 6, with a LOD score of 4.2; and chromosome 12, with a LOD score of 3.9. The LOD scores for chromosomes 6 and 12 are difficult to interpret, because they occurred only at the extreme ends of the chromosomes. The greatest gain provided by the SNP markers was a large increase in the linkage information content, with an average information content of 61% for the SNPs, versus an average of 41% for the microsatellite markers. The strengths and weaknesses of microsatellite versus SNP markers are illustrated by the results of our genome linkage scans. 相似文献
14.
Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22 总被引:3,自引:0,他引:3
Fallin MD Lasseter VK Wolyniec PS McGrath JA Nestadt G Valle D Liang KY Pulver AE 《American journal of human genetics》2003,73(3):601-611
Previous linkage studies in schizophrenia have been discouraging due to inconsistent findings and weak signals. Genetic heterogeneity has been cited as one of the primary culprits for such inconsistencies. We have performed a 10-cM autosomal genomewide linkage scan for schizophrenia susceptibility regions, using 29 multiplex families of Ashkenazi Jewish descent. Although there is no evidence that the rate of schizophrenia among the Ashkenazim differs from that in other populations, we have focused on this population in hopes of reducing genetic heterogeneity among families and increasing the detectable effects of any particular locus. We pursued both allele-sharing and parametric linkage analyses as implemented in Genehunter, version 2.0. Our strongest signal was achieved at chromosome 10q22.3 (D10S1686), with a nonparametric linkage score (NPL) of 3.35 (genomewide empirical P=.035) and a dominant heterogeneity LOD score (HLOD) of 3.14. Six other regions gave NPL scores >2.00 (on chromosomes 1p32.2, 4q34.3, 6p21.31, 7p15.2, 15q11.2, and 21q21.2). Upon follow-up with an additional 23 markers in the chromosome 10q region, our peak NPL score increased to 4.27 (D10S1774; empirical P=.00002), with a 95% confidence interval of 12.2 Mb for the location of the trait locus (D10S1677 to D10S1753). We find these results encouraging for the study of schizophrenia among Ashkenazi families and suggest further linkage and association studies in this chromosome 10q region. 相似文献
15.
Xiong DH Wang JT Wang W Guo YF Xiao P Shen H Jiang H Chen Y Deng H Drees B Recker RR Deng HW 《Human biology; an international record of research》2007,79(6):593-608
Osteoporosis is a common disease with strong genetic control. We performed an autosomal linkage scan in a large pedigree-based sample of 4,498 subjects for a composite osteoporosis phenotype that combines osteoporotic fracture (OF) and low bone mineral density (BMD). All of the subjects were U.S. Caucasians recruited in the Omaha area of Nebraska. Sex-specific linkage analyses and autosomal imprinting analyses were also conducted. For conventional linkage analyses in the total sample, we identified suggestive linkage on chromosomes 14q32 (LOD = 2.61), 7p14 (LOD = 2.42), and 11q25 (LOD = 2.09). In female subjects a significant linkage signal was detected on chromosome 14q22 (LOD = 3.53) and another two peaks were detected on chromosomes 7p14 (LOD = 3.07) and 9p21 (LOD = 2.29). Suggestive evidence of imprinted loci was found with paternally derived alleles on chromosomes 1q42 (LOD = 2.12) and 9q34 (LOD = 1.88). Some evidence of linkage to maternally derived alleles was found on chromosome 7q22 (LOD = 1.67). Our study provides new clues to osteoporosis genetic research and for the first time suggests that genomic imprinting effects may play a role in the etiology of osteoporosis. 相似文献
16.
Bossé Y Chagnon YC Després JP Rice T Rao DC Bouchard C Pérusse L Vohl MC 《Journal of lipid research》2004,45(3):419-426
A genome-wide linkage study was performed to identify chromosomal regions harboring genes influencing lipid and lipoprotein levels. Linkage analyses were conducted for four quantitative lipoprotein/lipid traits, i.e., total cholesterol, triglyceride, HDL-cholesterol (HDL-C), and LDL-C concentrations, in 930 subjects enrolled in the Québec Family Study. A maximum of 534 pairs of siblings from 292 nuclear families were available. Linkage was tested using both allele-sharing and variance-component linkage methods. The strongest evidence of linkage was found on chromosome 12q14.1 at marker D12S334 for HDL-C, with a logarithm of the odds (LOD) score of 4.06. Chromosomal regions harboring quantitative trait loci (QTLs) for LDL-C included 1q43 (LOD = 2.50), 11q23.2 (LOD = 3.22), 15q26.1 (LOD = 3.11), and 19q13.32 (LOD = 3.59). In the case of triglycerides, three markers located on 2p14, 11p13, and 11q24.1 provided suggestive evidence of linkage (LOD > 1.75). Tests for total cholesterol levels yielded significant evidence of linkage at 15q26.1 and 18q22.3 with the allele-sharing linkage method, but the results were nonsignificant with the variance-component method. In conclusion, this genome scan provides evidence for several QTLs influencing lipid and lipoprotein levels. Promising candidate genes were located in the vicinity of the genomic regions showing evidence of linkage. 相似文献
17.
Slager SL Schaid DJ Cunningham JM McDonnell SK Marks AF Peterson BJ Hebbring SJ Anderson S French AJ Thibodeau SN 《American journal of human genetics》2003,72(3):759-762
Regions on chromosomes 7 and 19 were recently reported to contain susceptibility loci that regulate tumor aggressiveness of prostate cancer. To confirm these findings, we analyzed genome scan data from 161 pedigrees affected with prostate cancer. Using the Gleason score as a quantitative measure of tumor aggressiveness, we regressed the squared trait difference, as well as the mean-corrected cross product, on the estimated proportion of alleles shared identical-by-descent at each marker position. Our results confirm the previous linkage results for chromosome 19q (D19S902, P<.00001). In addition, we report suggestive evidence for linkage on chromosome 4 (D4S403, P=.00012). The results of previous findings, together with our results, provide strong evidence that chromosome 19 harbors a gene for tumor aggressiveness. 相似文献
18.
Pankratz N Nichols WC Uniacke SK Halter C Rudolph A Shults C Conneally PM Foroud T;Parkinson Study Group 《American journal of human genetics》2003,72(4):1053-1057
Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility. 相似文献
19.
An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. 总被引:28,自引:11,他引:17
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R L Hanson M G Ehm D J Pettitt M Prochazka D B Thompson D Timberlake T Foroud S Kobes L Baier D K Burns L Almasy J Blangero W T Garvey P H Bennett W C Knowler 《American journal of human genetics》1998,63(4):1130-1138
Genetic factors influence the development of type II diabetes mellitus, but genetic loci for the most common forms of diabetes have not been identified. A genomic scan was conducted to identify loci linked to diabetes and body-mass index (BMI) in Pima Indians, a Native American population with a high prevalence of type II diabetes. Among 264 nuclear families containing 966 siblings, 516 autosomal markers with a median distance between adjacent markers of 6.4 cM were genotyped. Variance-components methods were used to test for linkage with an age-adjusted diabetes score and with BMI. In multipoint analyses, the strongest evidence for linkage with age-adjusted diabetes (LOD = 1.7) was on chromosome 11q, in the region that was also linked most strongly with BMI (LOD = 3.6). Bivariate linkage analyses strongly rejected both the null hypothesis of no linkage with either trait and the null hypothesis of no contribution of the locus to the covariation among the two traits. Sib-pair analyses suggest additional potential diabetes-susceptibility loci on chromosomes 1q and 7q. 相似文献
20.
Genome scan meta-analysis of schizophrenia and bipolar disorder,part III: Bipolar disorder 总被引:13,自引:3,他引:10
Segurado R Detera-Wadleigh SD Levinson DF Lewis CM Gill M Nurnberger JI Craddock N DePaulo JR Baron M Gershon ES Ekholm J Cichon S Turecki G Claes S Kelsoe JR Schofield PR Badenhop RF Morissette J Coon H Blackwood D McInnes LA Foroud T Edenberg HJ Reich T Rice JP Goate A McInnis MG McMahon FJ Badner JA Goldin LR Bennett P Willour VL Zandi PP Liu J Gilliam C Juo SH Berrettini WH Yoshikawa T Peltonen L Lönnqvist J Nöthen MM Schumacher J Windemuth C Rietschel M Propping P Maier W Alda M Grof P 《American journal of human genetics》2003,73(1):49-62
Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for “very narrow” (i.e., BP-I and schizoaffective disorder–BP) and “narrow” (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A “broad” model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region. 相似文献