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1.
Febrile seizures (FS) are common in children, and the incidence is 2–5% before the age of 5 years. A four-generation Chinese
family with autosomal dominant febrile seizure and epilepsy was studied by genome-wide linkage analysis. Significant linkage
was identified with markers on chromosome 3q26.2–26.33 with a maximum pairwise LOD score of >3.00. Fine mapping defined the
new genetic locus within a 10.7-Mb region between markers D3S3656 and D3S1232. A maximum multipoint LOD score of 5.27 was detected at marker D3S1565. A previously reported CLCN2 gene for epilepsy was excluded as the disease-causing gene in the family by mutational analysis of all exons and exon–intron
boundaries of CLCN2 and by haplotype analysis. Mutation analysis of KCNMB2 and KCNMB3, which were two potassium-channel genes in this linkage region, did not reveal a disease causing mutation. Our results identified
another novel locus on chromosome 3q26.2–26.33, and future studies of the candidate genes at the locus will identify a new
gene for combined FS and idiopathic epilepsies.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
X.-H. Dai, W.-W. Chen, and X. Wang contributed equally to this work. 相似文献
2.
Rinki Ratnapriya Joseph Vijai Jayaram S. Kadandale Rajesh S. Iyer Kurupath Radhakrishnan Anuranjan Anand 《Human genetics》2010,128(2):123-130
We performed a whole genome linkage analysis in a three-generation south Indian family with multiple members affected with
juvenile myoclonic epilepsy (JME). The maximum two-point LOD score obtained was 3.32 at recombination fraction (θ) = 0 for
D2S2248. The highest multipoint score of 3.59 was observed for the genomic interval between D2S2322 and D2S2228 at the chromosomal
region 2q33–q36. Proximal and distal boundaries of the critical genetic interval were defined by D2S116 and D2S2390, respectively.
A 24-Mb haplotype was found to co-segregate with JME in the family. While any potentially causative variant in the functional
candidate genes, SLC4A3, SLC23A3, SLC11A1 and KCNE4, was not detected, we propose to examine brain-expressed NRP2, MAP2, PAX3, GPR1, TNS1 and DNPEP, and other such positional candidate genes to identify the disease-causing gene for the disorder. 相似文献
3.
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
4.
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
5.
Xing Q Chen X Wang M Bai W Peng X Gao R Wu S Qian X Qin W Gao J Feng G He L 《Human genetics》2005,117(2-3):154-159
Generalized lentiginosis (GL) is characterized by widespread lentigines without associated noncutaneous abnormalities. In this study we performed a genome-wide linkage search in a Chinese family with GL and localized the familial GL locus to chromosome 4q21.1–q22.3, with a maximum two-point LOD score of 3.01 for D4S395 and D4S423 at a recombination fraction of 0. Multipoint analysis (maximum LOD score of 5.08 between markers D4S395 and D4S1563) and haplotype construction showed strong evidence of linkage in a region of 20 Mb flanked by markers D4S2915 and D4S1560 on chromosome 4q21.1–q22.3. This is the first report of linkage for GL, and it will provide further insight into the controversy of whether GL is an entity distinct from LEOPARD syndrome.Qinghe Xing and Xiangdong Chen contributed equally to this work 相似文献
6.
Chromosome 1q has previously been linked to bone mineral density (BMD) variation in the general population in several genome-wide linkage studies in both humans and mouse model. The aim of present study is to replicate and fine map the QTL influencing BMD in chromosome 1q in southern Chinese. Twelve microsatellite markers were genotyped for a 57 cΜ region in the chromosome 1q in 306 southern Chinese families with 1,459 subjects. Each of these families was ascertained through a proband with BMD Z-scores less than −1.3 at the hip or spine. BMD (g/cm2) at the L1-4 lumbar spine, femoral neck (FN), trochanter and total hip was measured by dual-energy X-ray absortiometry. Linkage analyses were performed using the variance component linkage analysis method implemented in Merlin software. Four markers (D1S2878, D1S196, D1S452, and D1S218) achieved a LOD score greater than 1.0 with spine BMD, with the maximum multipoint LOD score of 2.36 at the marker D1S196. We did not detect a LOD score greater than 1.0 for BMD at the FN, trochanter, or total hip in multipoint linkage analyses. Our results present the first evidence for the presence of an osteoporosis susceptibility gene on chromosome 1q in non-Caucasian subjects. Further analyses of candidate genes are warranted to identify QTL genes and variants underlying the variations of BMD in this region. 相似文献
7.
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
8.
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
9.
Singh RK Indra D Mitra S Mondal RK Basu PS Roy A Roychowdhury S Panda CK 《Human genetics》2007,122(1):71-81
The aim of this study was to locate the candidate tumor suppressor genes (TSGs) loci in the chromosomal 4p15-16, 4q22-23 and
4q34-35 regions associated with the development of uterine cervical carcinoma (CA-CX). Deletion mapping of the regions by
microsatellite markers identified six discrete areas with high frequency of deletions, viz. 4p16.2 (D1: 40%), 4p15.31 (D2:
35–38%), 4p15.2 (D3: 37–40%), 4q22.2 (D4: 34%), 4q34.2-34.3 (D5: 37–59%) and 4q35.1 (D6: 40–50%). Significant correlation
was noted among the deleted regions D1, D2 and D3. The deletions in D1, D2, D5 and D6 regions are suggested to be associated
with the cervical intraepithelial neoplasia (CIN), and deletions in the D2, D3, D5 and D6 regions seems to be associated with
progression of CA-CX. The deletions in the D2 and D6 regions showed significant prognostic implications (P = 0.001; 0.02). The expression of the candidate TSG SLIT2 mapped to D2 region gradually reduced from normal cervix uteri
→CIN → CA-CX. SLIT2 promoter hypermethylation was seen in 28% CIN samples and significantly increased with tumor progression
(P = 0.04). Significant correlation was seen between SLIT2 deletion and its promoter methylation (P = 0.001), indicating that both these phenomena could occur simultaneously to inactivate this gene. Immunohistochemical analysis
showed reduced expression of SLIT2 in cervical lesions and CA-CX cell lines. Although no mutation was detected in the SLIT2
promoter region (−432 to + 55 bp), CC and AA haplotypes were seen in −227 and −195 positions, respectively. Thus, it indicates
that inactivation of SLIT2-ROBO1 signaling pathway may have an important role in CA-CX development. 相似文献
10.
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
11.
Stuttering is a common speech disorder with substantial genetic contributions. To better understand the genetic factors involved
in stuttering, we performed a genome-wide linkage study in a newly-ascertained consanguineous stuttering family from Pakistan.
A linkage scan in this family using parametric linkage analysis revealed significant linkage only on chromosome 3q13.2–3q13.33,
with a maximum two-point LOD score of 4.23 under an autosomal recessive model of inheritance. 相似文献
12.
Deprez L Claes LR Claeys KG Audenaert D Van Dyck T Goossens D Van Paesschen W Del-Favero J Van Broeckhoven C De Jonghe P 《Human genetics》2006,118(5):618-625
Febrile seizures (FS) represent the most common seizure disorder in childhood and contribution of a genetic predisposition
has been clearly proven. In some families FS is associated with a wide variety of afebrile seizures. Generalized epilepsy
with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical febrile
seizures (FS+) and afebrile generalized and partial seizures. Mutations in the genes SCN1B, SCN1A and GABRG2 were identified in GEFS+ families. GEFS+ is genetically heterogeneous and mutations in these three genes were detected in
only a minority of the families. We performed a 10 cM density genome-wide scan in a multigenerational family with febrile
seizures and epilepsy and obtained a maximal multipoint LOD score of 3.12 with markers on chromosome 5q14.3-q23.1. Fine mapping
and segregation analysis defined a genetic interval of ≈33 cM between D5S2103 and D5S1975. This candidate region overlapped
with a previously reported locus for febrile seizures (FEB4) in the Japanese population, in which MASS1 was proposed as disease gene. Mutation analysis of the exons and exon–intron boundaries of MASS1 in our family did not reveal a disease causing mutation. Our linkage data confirm for the first time that a locus on chromosome
5q14-q23 plays a role in idiopathic epilepsies. However, our mutation data is negative and do not support a role for MASS1 suggesting that another gene within or near the FEB4 locus might exist. 相似文献
13.
Gul Naz Ghazanfar Ali Syed Kamran-ul-Hassan Naqvi Zahid Azeem Wasim Ahmad 《Human genetics》2010,127(4):395-401
Autosomal recessive hypotrichosis is a rare form of human genetic disorder characterized by sparse to absent hair on scalp
and rest of the body of affected individuals. Over the past few years at least five autosomal recessive forms of hypotrichosis
loci have been mapped on different human chromosomes. In the present study, we report localization of another novel autosomal
recessive hypotrichosis locus on human chromosome 10q11.23–22.3 in a four generation consanguineous Pakistani family. All
the four patients in the family showed typical features of hereditary hypotrichosis including sparse hair on the scalp and
rest of the body. Human genome scan using highly polymorphic microsatellite markers mapped the disease locus to a large region
on chromosome 10. This novel locus maps to 29.81 cM (28.5 Mb) region, flanked by markers D10S538 and D10S2327 on chromosome
10q11.23–22.3. A maximum multipoint LOD score of 3.26 was obtained with several markers in this region. DNA sequence analysis
of exons and splice-junction sites of four putative candidate genes (P4HA1, ZNF365, ZMYND17, MYST4), located in the linkage interval, were sequenced but were negative for functional sequence variants. 相似文献
14.
Localisation of a gene for Papillon-Lefèvre syndrome to chromosome 11q14–q21 by homozygosity mapping
Martin Walter Laass Hans Christian Hennies Sabine Preis Howard P. Stevens Martin Jung Irene M. Leigh Thomas F. Wienker André Reis 《Human genetics》1997,101(3):376-382
Papillon-Lefèvre syndrome is an autosomal recessively inherited palmoplantar keratoderma of unknown aetiology associated
with severe periodontitis leading to premature loss of dentition. Three consanguineous families, two of Turkish and one of
German origin, and three multiplex families, one of Ethiopian and two of German origin, with 11 affected and 6 unaffected
siblings in all were studied. A targeted genome search was initially attempted to several candidate gene regions but failed
to demonstrate linkage. Therefore a genome-wide linkage scan using a combination of homozygosity mapping and traditional linkage
analysis was undertaken. Linkage was obtained with marker D11S937 with a maximum two-point lod score of Z
max = 6.1 at recombination fraction θ = 0.00 on chromosome 11q14–q21 near the metalloproteinase gene cluster. Multipoint likelihood calculations gave a maximum
lod score of 7.35 between D11S901 and D11S1358. A 9.2-cM region homozygous by descent in the affected members of the three
consanguineous families lies between markers D11S1989 and D11S4176 harbouring the as yet unknown Papillon-Lefèvre syndrome
gene. Haplotype analyses in all the families studied support this localisation. This study has identified a further locus
harbouring a gene for palmoplantar keratoderma and one possibly involved in periodontitis.
Received: 19 July 1997 / Accepted: 22 August 1997 相似文献
15.
Bouzigon E Ulgen A Dizier MH Siroux V Lathrop M Kauffmann F Pin I Demenais F 《Human genetics》2007,121(6):711-719
Although many genome screens have been conducted for asthma as a binary trait, there is limited information regarding the
genetic factors underlying variation of asthma expression. Phenotypes related to variable disease expression include time
to asthma onset and variation in clinical expression as measured by an asthma score built from EGEA data. A recent genome
scan conducted for this score led to detection of a new region (18p11) not revealed by analysis of dichotomous asthma. Our
goal was to characterize chromosomal regions harboring genes underlying time to asthma onset and to search for pleiotropic
QTL influencing both time to asthma onset and the asthma score. We conducted a genome-wide linkage screen for time to asthma
onset, modeled by martingale residuals from Cox survival model, in EGEA families with at least two asthmatic sibs. This was
followed by a bivariate linkage scan of these residuals and asthma score. Univariate linkage analysis was performed using
the Maximum Likelihood Binomial method that we extended to bivariate analysis. This screen revealed two regions potentially
linked to time to asthma onset, 1p31 (LOD = 1.70, P = 0.003) and 5q13 (LOD = 1.87, P = 0.002). Bivariate linkage analysis led to a substantial improvement of the linkage signal on 5q13 (P = 0.00007), providing evidence for a pleiotropic QTL influencing both variation of time to asthma onset and of clinical expression.
Use of quantitative phenotypes of variable disease expression and suitable statistical methodology can improve the power to
detect new regions harboring genes which may play an important role in onset and course of disease. 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.
Hereditary lymphedema is a rare, lymphatic disorder resulting in the chronic swelling of the extremities. It shows wide inter-
and intra-familial clinical heterogeneity as well as variability in the age of onset. There are more than four genetically
distinct lymphedema conditions known and mutations in three genes have been discovered in families with lymphedema. However,
many other familial lymphedemas do not show linkage with the known loci, suggesting genetic heterogeneity. Here, we describe
a large inbred Pakistani family with congenital, progressive lymphedema confined to the lower limbs, which fades away at 40–45 years
of age. This condition segregates in an autosomal dominant fashion with reduced penetrance. The features are close to primary
lymphedema I, Nonne–Milory type (MIM 153100). We exclude this condition for linkage to the known loci for lymphedema by employing
highly polymorphic microsatellite markers from these intervals. Then, through a genome-wide linkage study we show that the
malformation in our family maps to chromosome 6q16.2–q22.1. The highest pair-wise LOD score (Z
max = 3.19) was obtained with microsatellite marker D6S1671, and a multipoint score of 3.75 was obtained at 108 cM. Haplotype
analysis indicated that the critical interval in this family flanks between markers D6S1716 and D6S303. Mutation analysis
in FOXO3, a likely candidate within this interval, did not show any pathogenic change in the affected family subjects. Our study provides
an evidence of a second locus for lymphedema type I. The discovery of the underlying gene could be helpful for the understanding
of this heterogeneous hereditary condition. 相似文献
18.
Martin LJ Ramachandran V Cripe LH Hinton RB Andelfinger G Tabangin M Shooner K Keddache M Benson DW 《Human genetics》2007,121(2):275-284
The aim of this study was to identify regions of the genome that harbor genes influencing inheritance of bicuspid aortic valve
(BAV) and/or associated cardiovascular malformation (CVM). Aortic valve disease is an important clinical problem, which often
results in valve replacement, the second most common cardiac surgery in the United States. In every age group, a majority
of cases of valve disease involves a BAV. BAV is the most common CVM with a reported prevalence of 1–2%. Heritability studies
indicate that BAV determination is almost entirely genetic. We used a family-based genome-wide linkage analysis with microsatellite
markers. Parametric and nonparametric analyses were performed with the software GENEHUNTER and SOLAR (Sequential Oligogenic
Linkage Analysis Routines). Thirty-eight families (353 subjects) with BAV and/or associated CVM were assessed. Each participant
underwent a standardized echocardiographic examination. The highest LOD score, 3.8, occurred on chromosome 18q between markers
D18S68 and D18S1161. Two other chromosomal regions, 5q15–21 (between D5S644 and D5S2027) and 13q33-qter (between D13S1265
and 13qter), exhibited suggestive evidence of linkage (LOD > 2.0). Further, two previously reported linkage peaks on 9q34
and 17q24 were replicated in family specific analyses. No significant X chromosome linkage peaks were identified. In this
genome-wide scan we demonstrate for the first time, that BAV and/or associated CVM exhibit linkage to chromosomes 18q, 5q
and 13q. These regions likely contain genes whose mutation results in BAV and/or associated CVM indicating their important
role in valvulogenesis and cardiac development.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Lisa J. Martin and Vijaya Ramachandran have contributed equally to this work. 相似文献
19.
20.
Leak TS Mychaleckyj JC Smith SG Keene KL Gordon CJ Hicks PJ Freedman BI Bowden DW Sale MM 《Human genetics》2008,124(1):63-71
Previously, we performed a genome scan for type 2 diabetes (T2DM) using 638 African-American (AA) affected sibling pairs from
247 families; non-parametric linkage analysis suggested evidence of linkage at 6q24–27 (LOD 2.26). To comprehensively evaluate
this region, we performed a two-stage association study by first constructing a SNP map of 754 SNPs selected from HapMap on
the basis of linkage disequilibrium (LD) in 300 AAT2DM end-stage renal disease (ESRD) subjects, 311 AA controls, 43 European
American controls and 45 Yoruba Nigerian samples (Set 1). Replication analyses were conducted in an independent population
of 283 AA T2DM-ESRD subjects and 282 AA controls (Set 2). In addition, we adjusted for the impact of admixture on association
results by using ancestry informative markers (AIMs). In Stage 1, 137 (18.2%) SNPs showed nominal evidence of association
(P < 0.05) in one or more of tests of association: allelic (n = 33), dominant (n = 36), additive (n = 29), or recessive (n = 34) genotypic models, and 2- (n = 47) and 3-SNP (n = 43) haplotypic analyses. These SNPs were selected for follow-up genotyping. Stage 2 analyses confirmed association with
a predicted 2-SNP “risk” haplotype in the PARK2 gene. Also, two intergenic SNPs showed consistent genotypic association with T2DM-ESRD: rs12197043 and rs4897081. Combined
analysis of all subjects from both stages revealed nominal associations with 17 SNPs within genes, including suggestive associations
in ESR1 and PARK2. This study confirms known diabetic nephropathy loci and identifies potentially novel susceptibility variants located within
6q24–27 in AA.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献