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1.
High plasma apolipoprotein B (apoB) and LDL cholesterol levels increase cardiovascular disease risk. These highly correlated measures may be partially controlled by common genetic polymorphisms. To identify chromosomal regions that contain genes causing low plasma levels of one or both parameters in Caucasian families ascertained for familial hypobetalipoproteinemia (FHBL), we conducted a whole-genome scan using 443 microsatellite markers typed in nine multigenerational families with at least two members with FHBL. Both variance components and regression-based linkage methods were used to identify regions of interest. Common linkage regions were identified for both measures on chromosomes 10q25.1-10q26.11 [maximum log of the odds (LOD) = 4.2 for LDL and 3.5 for apoB] and 6q24.3 (maximum LOD = 1.46 for LDL and 1.84 for apoB). There was also evidence for linkage to apoB on chromosome 13q13.2 (LOD = 1.97) and to LDL on chromosome 3p14.1 at 94 centimorgan (LOD = 1.52). Bivariate linkage analysis provided further evidence for loci contributing to both traits (6q24.3, LOD = 1.43; 10q25.1, LOD = 1.74). We evaluated single nucleotide polymorphisms (SNPs) in genes within our linkage regions to identify variants associated with apoB or LDL levels. The most significant finding was for rs2277205 in the 5' untranslated region of acyl-coenzyme A dehydrogenase short/branched chain and LDL (P = 10(-7)). Three additional SNPs were associated with apoB and/or LDL (P < 0.01). Although only the linkage signal on chromosome 10 reached genome-wide statistical significance, there are likely multiple chromosomal regions with variants that contribute to low levels of apoB and LDL and that may protect against coronary heart disease. 相似文献
2.
Genomewide scan for familial combined hyperlipidemia genes in finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels 总被引:10,自引:0,他引:10
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Pajukanta P Terwilliger JD Perola M Hiekkalinna T Nuotio I Ellonen P Parkkonen M Hartiala J Ylitalo K Pihlajamäki J Porkka K Laakso M Viikari J Ehnholm C Taskinen MR Peltonen L 《American journal of human genetics》1999,64(5):1453-1463
Familial combined hyperlipidemia (FCHL) is a common dyslipidemia predisposing to premature coronary heart disease (CHD). The disease is characterized by increased levels of serum total cholesterol (TC), triglycerides (TGs), or both. We recently localized the first locus for FCHL, on chromosome 1q21-q23. In the present study, a genomewide screen for additional FCHL loci was performed. In stage 1, we genotyped 368 polymorphic markers in 35 carefully characterized Finnish FCHL families. We identified six chromosomal regions with markers showing LOD score (Z) values >1.0, by using a dominant mode of inheritance for the FCHL trait. In addition, two more regions emerged showing Z>2.0 with a TG trait. In stage 2, we genotyped 26 more markers and seven additional FCHL families for these interesting regions. Two chromosomal regions revealed Z>2.0 in the linkage analysis: 10p11.2, Z=3.20 (theta=.00), with the TG trait; and 21q21, Z=2.24 (theta=.10), with the apoB trait. Furthermore, two more chromosomal regions produced Z>2.0 in the affected-sib-pair analysis: 10q11.2-10qter produced Z=2.59 with the TC trait and Z=2.29 with FCHL, and 2q31 produced Z=2.25 with the TG trait. Our results suggest additional putative loci influencing FCHL in Finnish families, some potentially affecting TG levels and some potentially affecting TC or apoB levels. 相似文献
3.
Genome scans provide evidence for low-HDL-C loci on chromosomes 8q23, 16q24.1-24.2, and 20q13.11 in Finnish families
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Soro A Pajukanta P Lilja HE Ylitalo K Hiekkalinna T Perola M Cantor RM Viikari JS Taskinen MR Peltonen L 《American journal of human genetics》2002,70(5):1333-1340
We performed a genomewide scan for genes that predispose to low serum HDL cholesterol (HDL-C) in 25 well-defined Finnish families that were ascertained for familial low HDL-C and premature coronary heart disease. The potential loci for low HDL-C that were identified initially were tested in an independent sample group of 29 Finnish families that were ascertained for familial combined hyperlipidemia (FCHL), expressing low HDL-C as one component trait. The data from the previous genome scan were also reanalyzed for this trait. We found evidence for linkage between the low-HDL-C trait and three loci, in a pooled data analysis of families with low HDL-C and FCHL. The strongest statistical evidence was obtained at a locus on chromosome 8q23, with a two-point LOD score of 4.7 under a recessive mode of inheritance and a multipoint LOD score of 3.3. Evidence for linkage also emerged for loci on chromosomes 16q24.1-24.2 and 20q13.11, the latter representing a recently characterized region for type 2 diabetes. Besides these three loci, loci on chromosomes 2p and 3p showed linkage in the families with low HDL-C and a locus on 2ptel in the families with FCHL. 相似文献
4.
Lilja HE Suviolahti E Soro-Paavonen A Hiekkalinna T Day A Lange K Sobel E Taskinen MR Peltonen L Perola M Pajukanta P 《Journal of lipid research》2004,45(10):1876-1884
Decreased HDL-cholesterol (HDL-C) and familial combined hyperlipidemia (FCHL) are the two most common familial dyslipidemias predisposing to premature coronary heart disease (CHD). These dyslipidemias share many phenotypic features, suggesting a partially overlapping molecular pathogenesis. This was supported by our previous pooled data analysis of the genome scans for low HDL-C and FCHL, which identified three shared chromosomal regions for a qualitative HDL-C trait on 8q23.1, 16q23.3, and 20q13.32. This study further investigates these regions as well as two other loci we identified earlier for premature CHD on 2q31 and Xq24 and a locus for high serum triglycerides (TGs) on 10q11. We analyzed 67 microsatellite markers in an extended study sample of 1,109 individuals from 92 low HDL-C or FCHL families using both qualitative and quantitative lipid phenotypes. These analyses provided evidence for linkage (a logarithm of odds score of 3.2) on 10q11 using a quantitative HDL-C trait. Importantly, this region, previously linked to TGs, body mass index, and obesity, provided evidence for association for quantitative TGs (P = 0.0006) and for a combined trait of HDL-C and TGs (P = 0.008) with marker D10S546. Suggestive evidence for linkage also emerged for HDL-C on 2q31 and for TGs on 20q13.32. Finnish families ascertained for dyslipidemias thus suggest that 10q11, 2q31, and 20q13.32 harbor loci for HDL-C and TGs. 相似文献
5.
A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11. 总被引:6,自引:0,他引:6
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B E Aouizerat H Allayee R M Cantor R C Davis C D Lanning P Z Wen G M Dallinga-Thie T W de Bruin J I Rotter A J Lusis 《American journal of human genetics》1999,65(2):397-412
Familial combined hyperlipidemia (FCHL) is a common familial lipid disorder characterized by a variable pattern of elevated levels of plasma cholesterol and/or triglycerides. It is present in 10%-20% of patients with premature coronary heart disease. The genetic etiology of the disease, including the number of genes involved and the magnitude of their effects, is unknown. Using a subset of 35 Dutch families ascertained for FCHL, we screened the genome, with a panel of 399 genetic markers, for chromosomal regions linked to genes contributing to FCHL. The results were analyzed by use of parametric-linkage methods in a two-stage study design. Four loci, on chromosomes 2p, 11p, 16q, and 19q, exhibited suggestive evidence for linkage with FCHL (LOD scores of 1.3-2.6). Markers within each of these regions were then examined in the original sample and in additional Dutch families with FCHL. The locus on chromosome 2 failed to show evidence for linkage, and the loci on chromosome 16q and 19q yielded only equivocal or suggestive evidence for linkage. However, one locus, near marker D11S1324 on the short arm of human chromosome 11, continued to show evidence for linkage with FCHL, in the second stage of this design. This region does not contain any strong candidate genes. These results provide evidence for a candidate chromosomal region for FCHL and support the concept that FCHL is complex and heterogeneous. 相似文献
6.
Positive evidence has been reported for linkage and association between the upstream stimulatory factor 1 gene (USF1) and familial combined hyperlipidemia (FCHL). We genotyped the two most positive single-nucleotide polymorphisms (SNPs) (usf1s1: rs3737787 and usf1s2: rs2073658) from previous studies in a large family sample. This sample included 2,195 subjects in 87 Utah pedigrees ascertained for early death due to coronary heart disease (CHD), early strokes, or early onset hypertension. There were a total of 262 relative pairs in these families with FCHL. In the full family sample, FCHL was associated with usf1s1 (P=0.02). Triglyceride and LDL cholesterol defined qualitatively or quantitatively were also associated with usf1s1 (P=0.02–0.05). Results were strengthened for qualitative and quantitative triglyceride and LDL cholesterol when data from males only was analyzed, revealing associations for usf1s1 (P=0.001–0.02), usf1s2 (P=0.02–0.05) and the haplotype of these two SNPs (P=0.01–0.04). The strongest results were in the subset of subjects from families ascertained for premature stroke or hypertension, rather than those ascertained for premature CHD. This study replicates the involvement of USF1 in FCHL and related lipid traits in a family sample not ascertained for FCHL. 相似文献
7.
Wijsman EM 《Human genetics》2012,131(10):1555-1563
Rare variation is the current frontier in human genetics. The large pedigree design is practical, efficient, and well-suited for investigating rare variation. In large pedigrees, specific rare variants that co-segregate with a trait will occur in sufficient numbers so that effects can be measured, and evidence for association can be evaluated, by making use of methods that fully use the pedigree information. Evidence from linkage analysis can focus investigation, both reducing the multiple testing burden and expanding the variants that can be evaluated and followed up, as recent studies have shown. The large pedigree design requires only a small fraction of the sample size needed to identify rare variants of interest in population-based designs, and many highly suitable, well-understood, and available statistical and computational tools already exist. Samples consisting of large pedigrees with existing rich phenotype and genome scan data should be prime candidates for high-throughput sequencing in the search of the determinants of complex traits. 相似文献
8.
Caitrin W. McDonough Meredith A. Bostrom Lingyi Lu Pamela J. Hicks Carl D. Langefeld Jasmin Divers Josyf C. Mychaleckyj Barry I. Freedman Donald W. Bowden 《Human genetics》2009,126(6):805-817
Genetic studies in Turkish, Native American, European American, and African American (AA) families have linked chromosome
18q21.1–23 to susceptibility for diabetes-associated nephropathy. In this study, we have carried out fine linkage mapping
in the 18q region previously linked to diabetic nephropathy in AAs by genotyping both microsatellite and single nucleotide
polymorphisms (SNPs) for linkage analysis in an expanded set of 223 AA families multiplexed for type 2 diabetes associated
ESRD (T2DM-ESRD). Several approaches were used to evaluate evidence of linkage with the strongest evidence for linkage in
ordered subset analysis with an earlier age of T2DM diagnosis compared to the remaining pedigrees (LOD 3.9 at 90.1 cM, ∆P = 0.0161, NPL P value = 0.00002). Overall, the maximum LODs and LOD-1 intervals vary in magnitude and location depending upon analysis. The
linkage mapping was followed up by performing a dense SNP map, genotyping 2,814 SNPs in the refined LOD-1 region in 1,029
AA T2DM-ESRD cases and 1,027 AA controls. Of the top 25 most associated SNPs, 10 resided within genic regions. Two candidate
genes stood out: NEDD4L and SERPINB7. SNP rs512099, located in intron 1 of NEDD4L, was associated under a dominant model of inheritance [P value = 0.0006; Odds ratio (95% Confidence Interval) OR (95% CI) = 0.70 (0.57–0.86)]. SNP rs1720843, located in intron 2
of SERPINB7, was associated under a recessive model of inheritance [P value = 0.0017; OR (95% CI) = 0.65 (0.50–0.85)]. Collectively, these results suggest that multiple genes in this region may
influence diabetic nephropathy susceptibility in AAs. 相似文献
9.
The APOA1-C3-A4-A5 gene complex encodes genes whose products are implicated in the metabolism of HDL and/or triglycerides. Although the relationship between polymorphisms in this gene cluster and dyslipidemias was first reported more than 15 years ago, association and linkage results have remained inconclusive. This is due, in part, to the oligogenic and multivariate nature of dyslipidemic phenotypes. Therefore, we investigate evidence of linkage of APOC3 and HDL using two samples of dyslipidemic pedigrees: familial combined hyperlipidemia (FCHL) and isolated low-HDL (ILHDL). We used a strategy that deals with several difficulties inherent in the study of complex traits: by using a Bayesian Markov Chain Monte Carlo (MCMC) approach we allow for oligogenic trait models, as well as simultaneous incorporation of covariates, in the context of multipoint analysis. By using this approach on extended pedigrees we provide evidence of linkage of APOC3 and HDL level variation in two samples with different ascertainment. In addition to APOC3, we estimate that two to three genes, each with a substantial effect on total variance, are responsible for HDL variation in both data sets. We also provide evidence, using the FCHL data set, for a pleiotropic effect between HDL, HDL3 and triglycerides at the APOC3 locus. 相似文献
10.
Common variants in the 5' region of the leptin gene are associated with body mass index in men from the National Heart, Lung, and Blood Institute Family Heart Study 总被引:3,自引:0,他引:3
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Jiang Y Wilk JB Borecki I Williamson S DeStefano AL Xu G Liu J Ellison RC Province M Myers RH 《American journal of human genetics》2004,75(2):220-230
11.
Human quantitative trait locus (QTL) linkage mapping, although based on classical statistical genetic methods that have been
around for many years, has been employed for genome-wide screening for only the last 10–15 years. In this time, there have
been many success stories, ranging from QTLs that have been replicated in independent studies to those for which one or more
genes underlying the linkage peak have been identified to a few with specific functional variants that have been confirmed
in in vitro laboratory assays. Despite these successes, there is a general perception that linkage approaches do not work
for complex traits, possibly because many human QTL linkage studies have been limited in sample size and have not employed
the family configurations that maximize the power to detect linkage. We predict that human QTL linkage studies will continue
to be productive for the next several years, particularly in combination with RNA expression level traits that are showing
evidence of regulatory QTLs of large effect sizes and in combination with high-density genome-wide SNP panels. These SNP panels
are being used to identify QTLs previously localized by linkage and linkage results are being used to place informative priors
on genome-wide association studies. 相似文献
12.
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
13.
Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans 总被引:19,自引:0,他引:19
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Duggirala R Blangero J Almasy L Dyer TD Williams KL Leach RJ O'Connell P Stern MP 《American journal of human genetics》1999,64(4):1127-1140
Since little is known about chromosomal locations harboring type 2 diabetes-susceptibility genes, we conducted a genomewide scan for such genes in a Mexican American population. We used data from 27 low-income extended Mexican American pedigrees consisting of 440 individuals for whom genotypic data are available for 379 markers. We used a variance-components technique to conduct multipoint linkage analyses for two phenotypes: type 2 diabetes (a discrete trait) and age at onset of diabetes (a truncated quantitative trait). For the multipoint analyses, a subset of 295 markers was selected on the basis of optimal spacing and informativeness. We found significant evidence that a susceptibility locus near the marker D10S587 on chromosome 10q influences age at onset of diabetes (LOD score 3.75) and is also linked with type 2 diabetes itself (LOD score 2.88). This susceptibility locus explains 63.8%+/-9.9% (P=. 000016) of the total phenotypic variation in age at onset of diabetes and 65.7%+/-10.9% (P=.000135) of the total variation in liability to type 2 diabetes. Weaker evidence was found for linkage of diabetes and of age at onset to regions on chromosomes 3p, 4q, and 9p. In conclusion, our strongest evidence for linkage to both age at onset of diabetes and type 2 diabetes itself in the Mexican American population was for a region on chromosome 10q. 相似文献
14.
Jasmin Divers Mich��le M. Sale Lingyi Lu Wei-Min Chen Kerry H. Lok Ida J. Spruill Jyotika K. Fernandes Carl D. Langefeld W. Timothy Garvey 《Journal of lipid research》2010,51(3):586-597
We sought to partition the genetic and environmental influences on lipoprotein subclasses and identify genomic regions that may harbor genetic variants that influence serum lipoprotein levels in a sample of Gullah-speaking African-Americans. We genotyped 5,974 SNPs in 979 subjects from 418 pedigrees and used the variance component approach to compute heritability estimates, genetic and environmental correlations, and linkage analyses for selected lipoprotein subclasses. The highest heritability estimate was observed for large VLDL particle concentration (0.56 ± 0.14). Mean LDL particle size and small LDL particle concentration (−0.94) had the strongest genetic correlation estimate. The highest logarithm of odds (LOD) score detected (3.0) was on chromosome 6p24 for small LDL particle concentration. The strongest signal, obtained with the reduced sample of diabetic individuals only, was observed on chromosome 20p13 for small LDL particle concentration. The highest bivariate linkage signal (LOD 2.4) was observed on chromosome 6p24 for mean LDL particle size and small LDL particle concentration.jlr Our results suggest a significant genetic contribution to multiple lipoprotein subclasses studied in this sample and that novel loci on chromosomes 6, 10, 16, and 20 may harbor genes contributing to small, atherogenic LDL particle concentration and large, triglyceride-rich VLDL particle concentration. 相似文献
15.
Selecting pedigrees for linkage analysis of a quantitative trait: the expected number of informative meioses. 总被引:1,自引:1,他引:0
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With evidence of segregation at a major locus for a quantitative trait having been found, a logical next step is to select a subset of the pedigrees to include in a linkage study to map the major locus. Ideally this subset should include much of the linkage information in the sample but include only a fraction of the pedigrees. We previously described a strategy for selecting pedigrees for linkage analysis of a quantitative trait on the basis of a pedigree likelihood-ratio statistic. For quantitative traits controlled by a major locus with a rare dominant allele, the likelihood-ratio strategy extracted nearly all the information for linkage while typically requiring marker data on only about one-third of the pedigrees. Here, we describe a new strategy to select pedigrees for linkage analysis on the basis of the expected number of potentially informative meioses in each pedigree. We demonstrate that this informative-meioses strategy provides an efficient and more general means to select pedigrees for a linkage study of a quantitative trait. 相似文献
16.
Schaid DJ McDonnell SK Zarfas KE Cunningham JM Hebbring S Thibodeau SN Eeles RA Easton DF Foulkes WD Simard J Giles GG Hopper JL Mahle L Moller P Badzioch M Bishop DT Evans C Edwards S Meitz J Bullock S Hope Q Guy M Hsieh CL Halpern J Balise RR Oakley-Girvan I Whittemore AS Xu J Dimitrov L Chang BL Adams TS Turner AR Meyers DA Friedrichsen DM Deutsch K Kolb S Janer M Hood L Ostrander EA Stanford JL Ewing CM Gielzak M Isaacs SD Walsh PC Wiley KE Isaacs WB Lange EM Ho LA Beebe-Dimmer JL Wood DP 《Human genetics》2006,120(4):471-485
While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening
stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms
could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer.
Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome
scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three
members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting
in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families.
Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1–14.3 (LOD = 2.4),
and 20p11.21–q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees
with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across
strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11,
LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13–22.3;
LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more
aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical
utility for men with aggressive prostate cancer and their relatives.
The names of all authors and their affiliations are listed in the Acknowledgements. The fact that Dr Schaid’s name is given
here for purposes of correspondence should not be taken to imply that he played the sole leading part in writing this article.
An erratum to this article can be found at 相似文献
17.
Gagnon F Jarvik GP Badzioch MD Motulsky AG Brunzell JD Wijsman EM 《Human genetics》2005,117(5):494-505
Several genome scans in search of high-density lipoprotein (HDL) quantitative trait loci (QTLs) have been performed. However, to date the actual identification of genes implicated in the regulation of common forms of HDL abnormalities remains unsuccessful. This may be due, in part, to the oligogenic and multivariate nature of HDL regulation, and potentially, pleiotropy affecting HDL and other lipid-related traits. Using a Bayesian Markov Chain Monte Carlo (MCMC) approach, we recently provided evidence of linkage of HDL level variation to the APOA1–C3–A4–A5 gene complex, in familial combined hyperlipidemia pedigrees, with an estimated number of two to three large QTLs remaining to be identified. We also presented results consistent with pleiotropy affecting HDL and triglycerides at the APOA1–C3–A4–A5 gene complex. Here we use the same MCMC analytic strategy, which allows for oligogenic trait models, as well as simultaneous incorporation of covariates, in the context of multipoint analysis. We now present results from a genome scan in search for the additional HDL QTLs in these pedigrees. We provide evidence of linkage for additional HDL QTLs on chromosomes 3p14 and 13q32, with results on chromosome 3 further supported by maximum parametric and variance component LOD scores of 3.0 and 2.6, respectively. Weaker evidence of linkage was also obtained for 7q32, 12q12, 14q31–32 and 16q23–24. 相似文献
18.
NL Parmalee C Schubert M Figueroa AC Bird T Peto MC Gillies PS Bernstein K Kiryluk JD Terwilliger R Allikmets;for the MacTel Project 《PloS one》2012,7(8):e24268
Macular Telangiectasia type 2 (MacTel) is a relatively rare macular disease of adult onset presenting with distortions in the visual field and leading to progressive loss of visual acuity. For the purpose of a gene mapping study, several pedigrees were ascertained with multiple affected family members. Seventeen families with a total of 71 individuals (including 45 affected or possibly affected) were recruited at clinical centers in 7 countries under the auspices of the MacTel Project. The disease inheritance was consistent with autosomal dominant segregation with reduced penetrance. Genome-wide linkage analysis was performed, followed by analysis of recombination breakpoints. Linkage analysis identified a single peak with multi-point LOD score of 3.45 on chromosome 1 at 1q41-42 under a dominant model. Recombination mapping defined a minimal candidate region of 15.6 Mb, from 214.32 (rs1579634; 219.96 cM) to 229.92 Mb (rs7542797; 235.07 cM), encompassing the 1q41-42 linkage peak. Sanger sequencing of the top 14 positional candidates genes under the linkage peak revealed no causal variants in these pedigrees. 相似文献
19.
Significant Linkage Evidence for a Predisposition Gene for Pelvic Floor Disorders on Chromosome 9q21
Kristina Allen-Brady Peggy A. Norton Craig Teerlink 《American journal of human genetics》2009,84(5):678-682
Predisposition factors for pelvic floor disorders (PFDs), including pelvic organ prolapse (POP), stress urinary incontinence (SUI), urge urinary incontinence (UUI), and hernias, are not well understood. We assessed linkage evidence for PFDs in mostly sister pairs who received treatment for moderate-to-severe POP. We genotyped 70 affected women of European descent from 32 eligible families with at least two affected cases by using the Illumina 1 million single-nucleotide polymorphism (SNP) marker set. Parametric linkage analysis with general dominant and recessive models was performed by the Markov chain Monte Carlo linkage analysis method, MCLINK, and a set of SNPs was formed, from which those in high linkage disequilibrium were eliminated. Significant genome-wide evidence for linkage was identified on chromosome 9q21 with a HLOD score of 3.41 under a recessive model. Seventeen pedigrees (53%) had at least nominal evidence for linkage on a by-pedigree basis at this region. These results provide evidence for a predisposition gene for PFDs on chromosome 9q. 相似文献
20.
Recently, a quantitative-trait locus (QTL) for whole blood serotonin level was identified in a genomewide linkage and association study in a founder population. Because serotonin level is a sexually dimorphic trait, in the present study, we evaluated the sex-specific genetic architecture of whole blood serotonin level in the same population. Here, we use an extended homozygosity-by-descent linkage method that is suitable for large complex pedigrees. Although both males and females have high broad heritability (H2=0.99), females have a higher additive component (h2=0.63 in females; h2=0.27 in males). Furthermore, the serotonin QTL on 17q that was identified previously in this population, integrin beta 3 (ITGB3), and a novel locus on 2q influence serotonin levels only in males, whereas linkage to a region on chromosome 6q is specific to females. Both sexes contribute to linkage signals on 12q and 16p. There were, overall, more associations meeting criteria for suggestive significance in males than in females, including those of ITGB3 and the serotonin transporter gene (5HTT). This analysis is consistent with heritable sexual dimorphism in whole blood serotonin levels resulting from the effects of a combination of sex-specific and sex-independent loci. 相似文献