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1.
Linkage between atopy and the IgE high-affinity receptor gene at 11q13 in atopic dermatitis families 总被引:9,自引:0,他引:9
R. Fölster-Holst Hans W. Moises L. Yang Wolfgang Fritsch Jean Weissenbach Enno Christophers 《Human genetics》1998,102(2):236-239
Atopic dermatitis is a common skin disease frequently associated with allergic disorders such as allergic rhinitis and asthma.
Controversial linkage findings between atopy and markers at chromosome 11q13 led us to search chromosome 11 for genes conferring
susceptibility to atopic dermatitis and atopy. Twelve families were investigated using highly polymorphic markers and a powerful
model-free linkage test. Two markers gave evidence for linkage, D11S903 (P = 0.02) and FCER1B (P = 0.005). A two-point lod-score analysis between these two markers revealed significant evidence for linkage (z
max = 4.02 at (θ = 0.0). In regard to model-dependent lod-score analyses between atopic disorders and FCER1B, two-point analysis gave a lod
score of z = 0.78 whereas two-locus analysis using a recessive-dominant mode of inheritance displayed a significant lod score of z = 3.55. Only 2 of 12 families showed evidence for linkage using the latter oligogenic model. In conclusion, the results of
our study map the FCER1B gene in close proximity to D11S903, support the finding of Cookson et al. implicating the IgE high-affinity
receptor gene (FCER1B) at 11q13, and furthermore suggest an oligogenic mode of inheritance as well as heterogeneity in the
genetic susceptibility to atopy and atopic dermatitis.
Received: 6 November 1995 / Accepted: 1 October 1997 相似文献
2.
Guilloud-Bataille M Bouzigon E Annesi-Maesano I Bousquet J Charpin D Gormand F Hochez J Just J Lemainque A Le Moual N Matran R Neukirch F Oryszczyn MP Paty E Pin I Vervloet D Kauffmann F Lathrop M Demenais F Dizier MH 《Human genetics》2008,122(6):605-614
Asthma, allergic rhinitis (AR) and atopic dermatitis also called eczema are allergic co-morbidites, which are likely to depend
on pleiotropic genetic effects as well as on specific genetic factors. After a previous genome-wide linkage screen conducted
for asthma and AR in a sample of 295 French EGEA families ascertained through asthmatic subjects, the aim here was to search
for genetic factors involved in eczema and more particularly the ones shared by the three allergic diseases using the same
EGEA data. In this sake, eczema and phenotypes of “allergic disease” accounting for the joint information on the presence/absence
of the three diseases were examined by linkage analyses using the maximum likelihood binomial method. A fine mapping was carried
out in regions detected for potential linkage, followed by association studies using the family-based association test (FBAT).
Evidence for linkage to 11p14 region was shown for “allergic disease” and eczema. Linkage was also indicated between eczema
and 5q13 and between “allergic disease” and both 5p15 and 17q21 regions. Fine mapping supported the evidence of linkage to
11p14 and FBAT analyses showed the association between “allergic disease” and a marker located at the linkage peak on 11p14.
Further investigations in this region will allow identifying genetic factor(s) which could have pleiotropic effect in the
three allergic diseases. 相似文献
3.
Yokouchi Y Nukaga Y Shibasaki M Noguchi E Kimura K Ito S Nishihara M Yamakawa-Kobayashi K Takeda K Imoto N Ichikawa K Matsui A Hamaguchi H Arinami T 《Genomics》2000,66(2):152-160
Childhood-onset asthma is frequently found in association with atopy. Although asthmatic children may develop IgE antibodies against variety of allergens, asthma is associated primarily with allergy to house-dust mites, molds, or other allergens. In this study, we conducted a genome-wide linkage search in 47 Japanese families (197 members) with more than two mite-sensitive atopic asthmatics (65 affected sib-pairs) using 398 markers. Multipoint linkage analysis was carried out for atopic asthma as a qualitative trait using the MAPMAKER/SIB program. We observed significant evidence for linkage with maximum lod scores (MLS) of 4.8 near the interleukin 12 B gene locus on chromosome 5q31-q33. In addition, suggestive evidence on 4q35 with MLS = 2.7 and on 13q11 with MLS = 2.4 was obtained. The other possible linkage regions included 6p22-p21.3 (MLS = 2.1), 12q21-q23 (MLS = 1.9), and 13q14.1-q14.3 (MLS = 2.0). Many of the linkage loci suggested in this study were at or close to those suggested by genome-wide studies for asthma in Caucasian populations. The present study suggests the contribution of the interleukin 12 B gene or nearby gene(s) to mite-sensitive atopic asthma and a considerable number of genetic variants common across Caucasians and Japanese populations contributing to asthma, although the relative importance of various variants may differ between the groups. 相似文献
4.
Elena S. Gusareva Helena Havelková Hana Blažková Marcela Kosařová Petr Kučera Vlastimil Král Daria Salyakina Bertram Müller-Myhsok Marie Lipoldová 《Immunogenetics》2009,61(1):15-25
Atopy is a predisposition to hyperproduction of immunoglobulin E (IgE) against common environmental allergens. It is often
associated with development of allergic diseases such as asthma, rhinitis, and dermatitis. Production of IgE is influenced
by genetic and environmental factors. In spite of progress in the study of heredity of atopy, the genetic mechanisms of IgE
regulation have not yet been completely elucidated. The analysis of complex traits can benefit considerably from integration
of human and mouse genetics. Previously, we mapped a mouse IgE-controlling locus Lmr9 on chromosome 4 to a segment of <9 Mb. In this study, we tested levels of total IgE and 25 specific IgEs against inhalant
and food allergens in 67 Czech atopic families. In the position homologous to Lmr9 on chromosome 8q12 marked by D8S285, we demonstrated a novel human IgE-controlling locus exhibiting suggestive linkage to
composite inhalant allergic sensitization (limit of detection, LOD = 2.11, P = 0.0009) and to nine specific IgEs, with maximum LOD (LOD = 2.42, P = 0.0004) to plantain. We also tested 16 markers at previously reported chromosomal regions of atopy. Linkage to plant allergens
exceeding the LOD > 2.0 was detected at 5q33 (D5S1507, LOD = 2.11, P = 0.0009) and 13q14 (D13S165, LOD = 2.74, P = 0.0002). The significant association with plant allergens (quantitative and discrete traits) was found at 7p14 (D7S2250,
corrected P = 0.026) and 12q13 (D12S1298, corrected P = 0.043). Thus, the finding of linkage on chromosome 8q12 shows precision and predictive power of mouse models in the investigation
of complex traits in humans. Our results also confirm the role of loci at 5q33, 7p14, 12q14, and 13q13 in control of IgE.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
5.
Xing C Sestak AL Kelly JA Nguyen KL Bruner GR Harley JB Gray-McGuire C 《Human genetics》2007,120(5):623-631
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by both population and phenotypic heterogeneity.
Our group previously identified linkage to SLE at 4p16 in European Americans (EA). In the present study we replicate this
linkage effect in a new cohort of 76 EA families multiplex for SLE by model-free linkage analysis. Using densely spaced microsatellite
markers in the linkage region, we have localized the potential SLE susceptibility gene(s) to be telomeric to the marker D4S2928
by haplotype construction. In addition, marker D4S394 showed marginal evidence of linkage disequilibrium with the putative
disease locus by the transmission disequilibrium test and significant evidence of association using a family-based association
approach as implemented in the program ASSOC. We also performed both two-point and multipoint model-based analyses to characterize
the genetic model of the potential SLE susceptibility gene(s), and the lod scores both maximized under a recessive model with
penetrances of 0.8. Finally, we performed a genome-wide scan of the total 153 EA pedigrees and evaluated the possibility of
interaction between linkage signals at 4p16 and other regions in the genome. Fourteen regions on 11 chromosomes (1q24, 1q42,
2p11, 2q32, 3p14.2, 4p16, 5p15, 7p21, 8p22, 10q22, 12p11, 12q24, 14q12, 19q13) showed evidence of linkage, among which, signals
at 2p11, 12q24 and 19q13 also showed evidence of interaction with that at 4p16. These results provide important additional
information about the SLE linkage effect at 4p16 and offer a unique approach to uncovering susceptibility loci involved in
complex human diseases. 相似文献
6.
Linkage and allelic association of chromosome 5 cytokine cluster genetic markers with atopy and asthma associated traits 总被引:5,自引:0,他引:5
Linkage and association of polymorphic markers in the chromosome 5q31-q33 cytokine cluster to atopy and asthma associated phenotypes have been reported by a number of groups. To investigate this region, 29 polymorphic markers were used to genotype a combined set of 233 families. These markers were ordered based upon the genetic data, supplemented by published genetic and physical maps. Significant two-point linkage was observed for asthma (most significant marker IRF1, P = 0.0002) and atopy (CD14SNP, P = 0.0001). Allelic association was observed between D5S463 and atopy (P = 0.002) and the skin prick test index (P = 0.04). The data support the possibility of three asthma/atopy loci in the 5q31-q33 region, each with a relatively small effect. 相似文献
7.
Genomewide Linkage Analysis of Stature in Multiple Populations Reveals Several Regions with Evidence of Linkage to Adult Height 总被引:18,自引:0,他引:18
Joel N. Hirschhorn Cecilia M. Lindgren Mark J. Daly Andrew Kirby Stephen F. Schaffner Noel P. Burtt David Altshuler Alex Parker John D. Rioux Jill Platko Daniel Gaudet Thomas J. Hudson Leif C. Groop Eric S. Lander 《American journal of human genetics》2001,69(1):106-116
Genomewide linkage analysis has been extremely successful at identification of the genetic variation underlying single-gene disorders. However, linkage analysis has been less successful for common human diseases and other complex traits in which multiple genetic and environmental factors interact to influence disease risk. We hypothesized that a highly heritable complex trait, in which the contribution of environmental factors was relatively limited, might be more amenable to linkage analysis. We therefore chose to study stature (adult height), for which heritability is approximately 75%-90% (Phillips and Matheny 1990; Carmichael and McGue 1995; Preece 1996; Silventoinen et al. 2000). We reanalyzed genomewide scans from four populations for which genotype and height data were available, using a variance-components method implemented in GENEHUNTER 2.0 (Pratt et al. 2000). The populations consisted of 408 individuals in 58 families from the Botnia region of Finland, 753 individuals in 183 families from other parts of Finland, 746 individuals in 179 families from Southern Sweden, and 420 individuals in 63 families from the Saguenay-Lac-St.-Jean region of Quebec. Four regions showed evidence of linkage to stature: 6q24-25, multipoint LOD score 3.85 at marker D6S1007 in Botnia (genomewide P<.06), 7q31.3-36 (LOD 3.40 at marker D7S2195 in Sweden, P<.02), 12p11.2-q14 (LOD 3.35 at markers D12S10990-D12S398 in Finland, P<.05) and 13q32-33 (LOD 3.56 at markers D13S779-D13S797 in Finland, P<.05). In a companion article (Perola et al. 2001 [in this issue]), strong supporting evidence is obtained for linkage to the region on chromosome 7. These studies suggest that highly heritable complex traits such as stature may be genetically tractable and provide insight into the genetic architecture of complex traits. 相似文献
8.
J Xu R C Levitt C I Panhuysen D S Postma E W Taylor P J Amelung K J Holroyd E R Bleecker D A Meyers 《American journal of human genetics》1995,57(2):425-430
Studies investigating the genetic control of total serum IgE levels are of major importance in understanding basic pathophysiologic mechanisms in atopy and asthma, since IgE levels predict onset and correlate with the clinical expression of these disorders. Previous analysis of data from 92 families, ascertained through a parent with asthma, showed evidence for recessive inheritance of high IgE levels with linkage to chromosome 5q. Since there was significant residual familial correlation in the one-locus segregation analysis, two-locus segregation and linkage analyses were performed. Segregation analyses provided evidence for a second major locus unlinked to the locus on 5q. Utilization of this two-locus model corroborates the previous evidence for linkage between this trait and markers on 5q31-q33. The LODs for the most informative marker D5S436 increased from 3.00 at 10% recombination to 4.67 at 9% recombination, when the two-locus model was used. Additional linkage studies are needed to map this second locus. These results demonstrate the importance of performing multilocus segregation and linkage analyses for quantitative traits that are related to the phenotype of a complex disorder. This approach has given further insight into the genetics of allergy and asthma by providing evidence for a two-locus model. 相似文献
9.
D. F. Wyszynski Nancy Maestri Iain McIntosh E. Anne Smith Amy F. Lewanda Constanza Garcia-Delgado Enrique Vinageras-Guarneros Eric Wulfsberg Terri H. Beaty 《Human genetics》1996,99(1):22-26
It has been reported that BCL3 on chromosome 19q, or a nearby gene, may play a role in the etiology of non-syndromic cleft
lip with or without cleft palate (NSCL/P) in some families. We tested 30 USA and 11 Mexican multiplex NSCL/P families for
four markers on chromosome 19q: D19S178, APOC2/AC1, APOC2/007, and BCL3. While likelihood-based linkage analysis failed to
show significant evidence of linkage, the transmission disequilibrium test indicated highly significant deviation from independent
assortment of allele 3 at the BCL3 marker in both data sets (USA:P = 0.001; Mexican: P = 0.018; both combined: P < 0.001) and for allele 13 of the D19S178 marker in the Mexican data set (P = 0.004). These results support an association, possibly due to linkage disequilibrium, between chromosome 19 markers and
a putative NSCL/P locus.
Received: 10 May 1996 / Revised: 31 July 1996 相似文献
10.
A genomewide search finds major susceptibility loci for nicotine dependence on chromosome 10 in African Americans
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Li MD Payne TJ Ma JZ Lou XY Zhang D Dupont RT Crews KM Somes G Williams NJ Elston RC 《American journal of human genetics》2006,79(4):745-751
Epidemiological studies have demonstrated that genetic factors account for at least 50% of the liability for nicotine dependence (ND). Although several linkage studies have been conducted, all samples to date were primarily of European origin. In this study, we conducted a genomewide scan of 1,261 individuals, representing 402 nuclear families, of African American (AA) origin. We examined 385 autosomal microsatellite markers for ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). After performing linkage analyses using various methods implemented in the GENEHUNTER and S.A.G.E. programs, we found a region near marker D10S1432 on chromosome 10q22 that showed a significant linkage to indexed SQ, with a maximum LOD score of 4.17 at 92 cM and suggestive linkage to HSI, SQ, and log-transformed SQ. Additionally, we identified three regions that met the criteria for suggestive linkage to at least one ND measure: on chromosomes 9q31 at marker D9S1825, 11p11 between markers D11S1993 and D11S1344, and 13q13 between markers D13S325 and D13S788. Other locations on chromosomes 15p11, 17q25, and 18q12 exhibited some evidence of linkage for ND (LOD >1.44). The four regions with significant or suggestive linkage were positive for multiple ND measures by multiple statistical methods. Some of these regions have been linked to smoking behavior at nominally significant levels in other studies, which provides independent replication of the regions for ND in different cohorts. In summary, we found significant linkage on chromosome 10q22 and suggestive linkage on chromosomes 9, 11, and 13 for major genetic determinants of ND in an AA sample. Further analysis of these positive regions by fine mapping and/or association analysis is thus warranted. To our knowledge, this study represents the first genomewide linkage scan of ND in an AA sample. 相似文献
11.
Quantitative-Trait Loci Influencing Body-Mass Index Reside on Chromosomes 7 and 13: The National Heart, Lung, and Blood Institute Family Heart Study
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Mary F. Feitosa Ingrid B. Borecki Stephen S. Rich Donna K. Arnett Phyliss Sholinsky Richard H. Myers Mark Leppert Michael A. Province 《American journal of human genetics》2002,70(1):72-82
Obesity is a risk factor for many chronic diseases, including glucose intolerance, lipid disorders, hypertension, and coronary heart disease. Even though the body-mass index (BMI) is a heterogeneous phenotype reflecting the amount of fat, lean mass, and body build, several studies have provided evidence of one or two major loci contributing to the variation in this complex trait. We sought to identify loci with potential influence on BMI in the data obtained from National Heart, Lung, and Blood Institute Family Heart Study. Two complementary samples were studied: (a) 1,184 subjects in 317 sibships, with 243 markers typed by the Utah Molecular Genetics Laboratory (UMGL) and (b) 3,027 subjects distributed among 401 three-generation families, with 404 markers typed by the Mammalian Genotyping Service (MGS). A genome scan using a variance-components-based linkage approach was performed for each sample, as well as for the combined sample, in which the markers from each analysis were placed on a common genetic map. There was strong evidence for linkage on chromosome 7q32.3 in each sample: the maximum multipoint LOD scores were 4.7 (P<10-5) at marker GATA43C11 and 3.2 (P=.00007) at marker D7S1804, for the MGS and UMGL samples, respectively. The linkage result is replicated by the consistent evidence from these two complementary subsets. Furthermore, the evidence for linkage was maintained in the combined sample, with a LOD score of 4.9 (P<10-5) for both markers, which map to the same location. This signal is very near the published location for the leptin gene, which is the most prominent candidate gene in this region. For the combined-sample analysis, evidence of linkage was also found on chromosome 13q14, with D13S257 (LOD score 3.2, P=.00006), and other, weaker signals (LOD scores 1.5-1.9) were found on chromosomes 1, 2, 3, 5, 6, 14, and 15. 相似文献
12.
Ekelund E Saaf A Tengvall-Linder M Melen E Link J Barker J Reynolds NJ Meggitt SJ Kere J Wahlgren CF Pershagen G Wickman M Nordenskjold M Kockum I Bradley M 《American journal of human genetics》2006,78(6):1060-1065
In a systematic analysis of global gene-expression patterns, we found that SOCS3 messenger RNA was significantly more highly expressed in skin from patients with atopic dermatitis than in skin from healthy controls, and immunohistochemical analysis confirmed a similar elevation of SOCS3 protein. Furthermore, we found a genetic association between atopic dermatitis and a haplotype in the SOCS3 gene in two independent groups of patients (P<.02 and P<.03). These results strongly suggest that SOCS3, located in a chromosomal region previously linked to the disease (17q25), is a susceptibility gene for atopic dermatitis. 相似文献
13.
Novel immunoglobulin superfamily gene cluster,mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility 总被引:9,自引:0,他引:9
Speckman RA Wright Daw JA Helms C Duan S Cao L Taillon-Miller P Kwok PY Menter A Bowcock AM 《Human genetics》2003,112(1):34-41
Chromosome 17q25 harbors a susceptibility locus for psoriasis ( PSORS2). This locus may overlap with loci for atopic dermatitis and rheumatoid arthritis. To further refine the location of PSORS2, we genotyped 242 primarily nuclear families for 15 polymorphic microsatellites mapping to chromosome 17q23-q25. Non-parametric linkage analysis revealed a linkage peak lying close to a novel cluster of genes from the immunoglobulin (Ig) superfamily. This cluster spans >250 kb and harbors five CMRF35-like genes and a sixth inhibitory receptor ( CMRF35H) with three ITIM motifs that is transcribed in the opposite direction from the rest. The Ig domains encoded by these genes are most similar to those of the TREM (triggering receptor expressed selectively in myeloid cells) molecules, NKp44 and the polymeric immunoglobulin receptor. CMRF35-like genes are only expressed in sub-populations of cells of the myeloid lineage. In order to investigate the association of this region with psoriasis, we genotyped the families for 13 novel microsatellites and 19 SNPs from the region of linkage. A maximum NPL of 1.6 ( P=0.05) was obtained within the interval. Two SNP-based haplotypes revealed some evidence for association with psoriasis. One spanned CMRF35H and includes a non-synonymous polymorphism within CMRF35H (R111Q) (TDT P=0.03). The second was a three-locus haplotype lying within the first intron of CMRF35A2 ( TREM5) (TDT P=0.04). The novel markers described here will facilitate additional linkage and association studies between the CMRF35 family and disease. 相似文献
14.
Evidence for asthma susceptibility genes on chromosome 11 in an African-American population 总被引:4,自引:0,他引:4
Huang SK Mathias RA Ehrlich E Plunkett B Liu X Cutting GR Wang XJ Li XD Togias A Barnes KC Malveaux F Rich S Mellen B Lange E Beaty TH;Comparative Study on the Genetics of Asthma 《Human genetics》2003,113(1):71-75
Initial genome-wide scan data provided suggestive evidence for linkage of the asthma phenotype in African-American (AA), but not Caucasian, families to chromosome 11q markers (peak at D11S1985; LOD=2). To refine this region, mapping analysis of 91 AA families (51 multiplex families and 40 asthmatic case-parent trios) was performed with an additional 17 markers flanking the initial peak linkage marker. Multipoint analyses of the 51 multiplex families yielded significant evidence of linkage with a peak non-parametric linkage score of 4.38 at marker D11S1337 (map position 68.6 cM). Furthermore, family-based association and transmission disequilibrium tests conducted on all 91 families showed significant evidence of linkage in the presence of disequilibrium for several individual markers in this region. A putative susceptibility locus was estimated to be at map position 70.8 cM with a confidence interval spanning the linkage peak. Evidence from both linkage and association analyses suggest that this region of chromosome 11 contains one or more susceptibility genes for asthma in these AA families. 相似文献
15.
Association of polymorphisms in the β2-adrenoreceptor gene with higher levels of parasitic infection
Claire E. Ramsay Catherine M. Hayden Katrina J. Tiller Paul R. Burton Isabel Hagel Miguel Palenque Neil R. Lynch Jack Goldblatt Peter N. LeSouëf 《Human genetics》1999,104(3):269-274
The diminishing incidence of parasitic infection in westernised societies has been suggested to result in an increased prevalance
of asthma. Asthma is a polygenic disease and genome screens have shown that genes on chromosome 5q31–33 are strongly linked
to the disease. The gene for the β2-adrenoreceptor is located in this region and two polymorphisms have been identified that result in amino acid changes at
positions 16 (ArgGly) and 27 (GlnGlu). To determine whether these polymorphisms influence asthma and parasitic infection,
a genotype/phenotype study has been performed on a cohort of 126 children from Coche Island in Venezuela. There is a high
incidence of asthma on the island and intestinal helminthiasis is endemic. Genotyping for both polymorphisms was carried out
by using the polymerase chain reaction and allele-specific oligonucleotide hybridisation. Genotype frequencies in this cohort
were consistent with other studies and both polymorphisms were in significant linkage disequilibrium. Individuals who were
homozygous for Arg16 had significantly higher levels of specific IgE to Ascaris lumbricoides (P=0.002), significantly higher A. lumbricoides egg counts (P=0.001) and significantly larger wheal sizes following skin-prick testing with A. lumbricoides allergen (P=0.008). There was no association between either polymorphism and total serum IgE or asthma in this population. A combination
of mast cell degranulation and the lung migratory phase of A. lumbricoides larvae may result in bronchoconstriction in infected individuals. These results suggest that the Gly 16 allele confers resistance
to high levels of parasitic infection in this population. An alternative explanation for the association is that it may be
the result of linkage disequilibrium with other genes in the chromosome 5q31–33 region.
Received: 25 November 1998 / Accepted: 30 January 1999 相似文献
16.
A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population 总被引:4,自引:0,他引:4
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Liu F Arias-Vásquez A Sleegers K Aulchenko YS Kayser M Sanchez-Juan P Feng BJ Bertoli-Avella AM van Swieten J Axenovich TI Heutink P van Broeckhoven C Oostra BA van Duijn CM 《American journal of human genetics》2007,81(1):17-31
Alzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All patients and their 170 closely related relatives were genotyped using 402 microsatellite markers. Extensive genealogy information was collected, which resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees, to reduce the computational burden of linkage analysis. Simulations aiming to evaluate the effect of pedigree splitting on false-positive probabilities showed that a LOD score of 3.64 corresponds to 5% genomewide type I error. Multipoint analysis revealed four significant and one suggestive linkage peaks. The strongest evidence of linkage was found for chromosome 1q21 (heterogeneity LOD [HLOD]=5.20 at marker D1S498). Approximately 30 cM upstream of this locus, we found another peak at 1q25 (HLOD=4.0 at marker D1S218). These two loci are in a previously established linkage region. We also confirmed the AD locus at 10q22-24 (HLOD=4.15 at marker D10S185). There was significant evidence of linkage of AD to chromosome 3q22-24 (HLOD=4.44 at marker D3S1569). For chromosome 11q24-25, there was suggestive evidence of linkage (HLOD=3.29 at marker D11S1320). We next tested for association between cognitive function and 4,173 single-nucleotide polymorphisms in the linked regions in an independent sample consisting of 197 individuals from the GRIP region. After adjusting for multiple testing, we were able to detect significant associations for cognitive function in four of five AD-linked regions, including the new region on chromosome 3q22-24 and regions 1q25, 10q22-24, and 11q25. With use of cognitive function as an endophenotype of AD, our study indicates the that the RGSL2, RALGPS2, and C1orf49 genes are the potential disease-causing genes at 1q25. Our analysis of chromosome 10q22-24 points to the HTR7, MPHOSPH1, and CYP2C cluster. This is the first genomewide screen that showed significant linkage to chromosome 3q23 markers. For this region, our analysis identified the NMNAT3 and CLSTN2 genes. Our findings confirm linkage to chromosome 11q25. We were unable to confirm SORL1; instead, our analysis points to the OPCML and HNT genes. 相似文献
17.
A second-generation genomewide screen for asthma-susceptibility alleles in a founder population 总被引:29,自引:0,他引:29
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A genomewide screen for asthma- and atopy-susceptibility loci was conducted, using 563 markers, in 693 Hutterites who are members of a single 15-generation pedigree, nearly doubling the sample size from the authors' earlier studies. The resulting increase in power led to the identification of 23 loci in 18 chromosomal regions showing evidence for linkage that is, in general, 10-fold more significant (P<.001 vs. P<.01) than the linkages reported previously in this population. Moreover, linkages to loci in 11 chromosomal regions were identified for the first time in the Hutterites in this report, including five regions (5p, 5q, 8p, 14q, and 16q) showing evidence both of linkage, by the likelihood ratio (LR) chi(2), and of disequilibrium, by the transmission/disequilibrium test. A region on chromosome 19 continues to show evidence for linkage, by both tests, in this study. Studies of 17 candidate genes provide evidence for association with variation in the IL4RA gene (16p12), the HLA class II genes (6p21), and the interferon-alpha gene cluster (9p22), but the lack of evidence for linkage in these regions by the LR chi(2) test suggests that these are minor susceptibility loci. A polymorphism in the CD14 gene is in linkage disequilibrium with an as yet unidentified susceptibility allele in the 5q cytokine cluster, a region showing evidence for linkage among the Hutterites. Finally, 10 of the regions showing evidence for linkage in the Hutterites have shown evidence of linkage to related phenotypes in other genome screens, suggesting that these regions may contain common alleles that have relatively large effects on asthma and atopy phenotypes in diverse populations. 相似文献
18.
Eckenrode S Marron MP Nicholls R Yang MC Yang JJ Guida Fonseca LC She JX 《Human genetics》2000,106(1):14-18
Previous studies have identified a susceptibility region for insulin-dependent (type 1) diabetes mellitus on chromosome 11q13 (IDDM4). In this study, 15 polymorphic markers were analyzed for 382 affected sibpair (ASP) families with type 1 diabetes. Our analyses provided additional evidence for linkage for IDDM4 (a peak LOD score of 3.4 at D11S913). The markers with strong linkage evidence are located within an interval of approximately 6 cM between D11S4205 and GALN. We also identified polymorphisms in two candidate genes, Fas-associated death domain protein (FADD) and galanin (GALN). Analyses of the data by transmission/disequilibrium test (TDT) and extended TDT (ETDT) did not provide any evidence for association/linkage with these candidate genes. However, ETDT did reveal significant association/linkage with the marker D11S987 (P=0.0004) within the IDDM4 interval defined by ASP analyses, suggesting that IDDM4 may be in the close proximity of D11S987. 相似文献
19.
Ulla Christensen Steffen Møller-Larsen Mette Nyegaard Annette Haagerup Anne Hedemand Charlotte Brasch-Andersen Torben A. Kruse Thomas Juhl Corydon Mette Deleuran Anders D. Børglum 《Human genetics》2009,126(4):549-557
Atopic dermatitis (AD) is a common, itchy skin disease of complex inheritance characterized by dermal and epidermal inflammation.
The heritability is considerable and well documented. To date, four genome scans have examined the AD phenotype, showing replicated
linkage at 3p26-22, 3q13-21 and 18q11-21. Our previous AD scan showed evidence of linkage to loci at 3p and 18q, and furthermore
at 4p15-14. In order to further investigate the genetic basis of AD, we collected and analysed a new Danish family sample
consisting of 130 AD sib pair families (555 individuals including 295 children with AD). AD was diagnosed after clinical examination,
AD severity was scored and specific IgE was determined. A linkage scan of chromosome 3, 4 and 18 was performed using 91 microsatellite
markers. Linkage analyses were performed of dichotomous phenotypes and semi-quantitative traits including the AD severity
score. We analysed the novel AD sample alone and together with the previously examined sample. AD severity showed a maximum
Z-score of 3.7 at 4q22.1 suggesting the localization of a novel gene for AD severity. A maximum MOD score of 4.6 was obtained
at 3p24 for the AD phenotype, providing the first significant linkage of AD at this locus. A maximum MLS score of 3.3 was
obtained at 3q21 for IgE-associated AD, and evidence of linkage was also obtained at 3p22.2-21.31, 3q13, 4q35, and 18q12.
The results presented should provide a firm basis for gene-targeting studies of AD and related disorders. 相似文献
20.
Jianjun Liu Suh-Hang Juo P?ivi Holopainen Joseph Terwilliger Xiaomei Tong Adina Grunn Miguel Brito Peter Green Kirsi Mustalahti Markku M?ki T. Conrad Gilliam Jukka Partanen 《American journal of human genetics》2002,70(1):51-59
Celiac disease (CD), or gluten-sensitive enteropathy, is a common multifactorial disorder resulting from intolerance to cereal prolamins. The only established genetic susceptibility factor is HLA-DQ, which appears to explain only part of the overall genetic risk. We performed a genomewide scan of CD in 60 Finnish families. In addition to strong evidence for linkage to the HLA region at 6p21.3 (Z(max)>5), suggestive evidence for linkage was found for six other chromosomal regions--1p36, 4p15, 5q31, 7q21, 9p21-23, and 16q12. We further analyzed the three most convincing regions--4p15, 5q31, and 7q21--by evaluation of dense marker arrays across each region and by analysis of an additional 38 families. Although multipoint analysis with dense markers provided supportive evidence (multipoint LOD scores 3.25 at 4p15, 1.49 at 5q31, and 1.04 at 7q21) for the initial findings, the additional 38 families did not strengthen evidence for linkage. The role that HLA-DQ plays was studied in more detail by analysis of DQB1 alleles in all 98 families. All but one patient carried one or two HLA-DQ risk alleles, and 65% of HLA-DQ2 carriers were affected. Our study indicates that the HLA region harbors a predominant CD-susceptibility locus in these Finnish families. 相似文献