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American Journal of Human Genetics Aug 1995With recent rapid advances in mapping of the human genome, including highly polymorphic and closely linked markers, studies of marker associations with disease are...
With recent rapid advances in mapping of the human genome, including highly polymorphic and closely linked markers, studies of marker associations with disease are increasingly relevant for mapping disease genes. The use of nuclear-family data in association studies was initially developed to avoid possible ethnic mismatching between patients and randomly ascertained controls. The parental marker alleles not transmitted to an affected child or never transmitted to an affected sib pair form the so-called AFBAC (affected family-based controls) population. In this paper, the theoretical foundation of the AFBAC method is proved for any single-locus model of disease and for any nuclear family-based ascertainment scheme. In a random-mating population, when there is a marker association with disease, the AFBAC population provides an unbiased estimate of the overall population (control) marker alleles when the recombination fraction (theta) between the marker and disease genes is sufficiently small that it can be taken as zero (theta = 0). With population stratification, only marker associations present in the subpopulations will be detected with family-based analyses. Of more importance, however, is the fact that, when theta not equal to 0, differences between transmitted parental (patient) marker allele frequencies and non- or never-transmitted parental marker allele frequencies (implying a marker association with disease) can only be observed for marker genes linked to a disease gene (theta < 1/2). Thus, associations of unlinked marker loci with disease at the population level, caused by population stratification, migration, or admixture, are eliminated. This validates the use of family-based association tests as an appropriate strategy for mapping disease genes.
Topics: Chromosome Mapping; Family; Genetic Diseases, Inborn; Genetic Linkage; Humans; Lod Score; Models, Genetic; Pedigree
PubMed: 7668275
DOI: No ID Found -
American Journal of Human Genetics Sep 1995Misspecification of transmission model parameters can produce artifactually negative lod scores at small recombination fractions and in multipoint analysis. To avoid...
Misspecification of transmission model parameters can produce artifactually negative lod scores at small recombination fractions and in multipoint analysis. To avoid this problem, we have tried to devise a test that aims to detect a genetic effect at a particular locus, rather than attempting to estimate the map position of a locus with specified effect. Maximizing likelihoods over transmission model parameters, as well as linkage parameters, can produce seriously biased parameter estimates and so yield tests that lack power for the detection of linkage. However, constraining the transmission model parameters to produce the correct population prevalence largely avoids this problem. For computational convenience, we recommend that the likelihoods under linkage and non-linkage are independently maximized over a limited set of transmission models, ranging from Mendelian dominant to null effect and from null effect to Mendelian recessive. In order to test for a genetic effect at a given map position, the likelihood under linkage is maximized over admixture, the proportion of families linked. Application to simulated data for a wide range of transmission models in both affected sib pairs and pedigrees demonstrates that the new method is well behaved under the null hypothesis and provides a powerful test for linkage when it is present. This test requires no specification of transmission model parameters, apart from an approximate estimate of the population prevalence. It can be applied equally to sib pairs and pedigrees, and, since it does not diminish the lod score at test positions very close to a marker, it is suitable for application to multipoint data.
Topics: Chromosome Mapping; Genetic Linkage; Genotype; Humans; Likelihood Functions; Lod Score; Models, Genetic
PubMed: 7668300
DOI: No ID Found -
The Journal of Heredity Dec 2019Multiparental advanced generation intercross (MAGIC) populations provide abundant genetic variation for use in plant genetics and breeding. In this study, we developed a...
Multiparental advanced generation intercross (MAGIC) populations provide abundant genetic variation for use in plant genetics and breeding. In this study, we developed a method for quantitative trait locus (QTL) detection in pure-line populations derived from 8-way crosses, based on the principles of inclusive composite interval mapping (ICIM). We considered 8 parents carrying different alleles with different effects. To estimate the 8 genotypic effects, 1-locus genetic model was first built. Then, an orthogonal linear model of phenotypes against marker variables was established to explain genetic effects of the locus. The linear model was estimated by stepwise regression and finally used for phenotype adjustment and background genetic variation control in QTL mapping. Simulation studies using 3 genetic models demonstrated that the proposed method had higher detection power, lower false discovery rate (FDR), and unbiased estimation of QTL locations compared with other methods. Marginal bias was observed in the estimation of QTL effects. An 8-parental recombinant inbred line (RIL) population previously reported in cowpea and analyzed by interval mapping (IM) was reanalyzed by ICIM and genome-wide association mapping implemented in software FarmCPU. The results indicated that ICIM identified more QTLs explaining more phenotypic variation than did IM; ICIM provided more information on the detected QTL than did FarmCPU; and most QTLs identified by IM and FarmCPU were also detected by ICIM.
Topics: Algorithms; Chromosome Mapping; Crosses, Genetic; Genetics, Population; Inbreeding; Lod Score; Models, Genetic; Quantitative Trait Loci; Vigna
PubMed: 31419284
DOI: 10.1093/jhered/esz050 -
American Journal of Human Genetics May 1997Preeclampsia (PE) and eclampsia (E) are potentially life-threatening conditions that can occur during human pregnancy. Generally considered to be different degrees of...
Preeclampsia (PE) and eclampsia (E) are potentially life-threatening conditions that can occur during human pregnancy. Generally considered to be different degrees of severity of the same disease process, the PE/E syndrome is thought to be predominantly genetic in origin, although its exact etiology and genetics are not fully understood. Here we report results of a genomewide linkage search for the gene(s) responsible for susceptibility to PE/E, using 15 informative pedigrees and 90 polymorphic DNA markers from all autosomes. Because of uncertainties concerning inheritance and diagnosis, four different models that assume maternal gene expression have been used to carry out LOD-score analysis. The region between D4S450 and D4S610 (2.8 cM) on the long arm of chromosome 4 was identified as a strong candidate region for a PE/E-susceptibility locus. The maximum multipoint LOD score within this interval was 2.9. Analysis of markers in the region around D4S450 and D4S610 by the affected-pedigree-member method also supported the possibility of a susceptibility locus in this region. However, to verify or exclude definitively linkage to this region, other groups of PE/E pedigrees will be required.
Topics: Australia; Chromosomes, Human, Pair 4; Eclampsia; Female; Genetic Markers; Genetic Predisposition to Disease; Humans; Lod Score; Models, Genetic; Pedigree; Pre-Eclampsia; Pregnancy; Syndrome
PubMed: 9150163
DOI: No ID Found -
American Journal of Human Genetics Aug 1993Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive primary disease of muscle which is usually inherited as an autosomal dominant disorder. FSHD has...
Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive primary disease of muscle which is usually inherited as an autosomal dominant disorder. FSHD has been localized to the long arm of chromosome 4, specifically to the 4q3.5-qter region. Initially published linkage studies showed no evidence for heterogeneity in FSHD. In the present study we have examined individuals in seven FSHD families. Two-point lod scores show significant evidence for linkage for D4S163 (lod score 3.04 at recombination fraction .21) and D4S139 (lod score 3.84 at recombination fraction .20). D4S171 also gave a positive score (lod score 2.56 at recombination fraction .24). Significant evidence for heterogeneity was found for each of the three markers. Multipoint linkage analysis in this region resulted in a peak multipoint lod score of 6.47. The multipoint analysis supported the two-point studies with odds of 20:1 showing linkage and heterogeneity over linkage and homogeneity. Five of the seven families gave a posterior probability of > 95% of being of the linked type, while two families appeared unlinked to this region of 4q (P < .01%). Individuals in the two unlinked families met the clinical criteria for the diagnosis of FSHD, including facial weakness, clavicular flattening, scapula winging, proximal muscle weakness, and myopathic changes on muscle biopsies without inflammatory or mitochondrial pathology. This study demonstrates genetic heterogeneity in FSHD and has important implications for both genetic counseling and the elucidation of the etiology of FSHD.
Topics: Chi-Square Distribution; Chromosome Mapping; Chromosomes, Human, Pair 4; Female; Genes, Dominant; Genetic Linkage; Genetic Variation; Humans; Lod Score; Middle Aged; Muscular Dystrophies; Pedigree
PubMed: 8328457
DOI: No ID Found -
PloS One Jan 2008A powerful way to identify genes for complex traits it to combine genetic and genomic methods. Many trait quantitative trait loci (QTLs) for complex traits are sex...
BACKGROUND
A powerful way to identify genes for complex traits it to combine genetic and genomic methods. Many trait quantitative trait loci (QTLs) for complex traits are sex specific, but the reason for this is not well understood.
METHODOLOGY/PRINCIPAL FINDINGS
RNA was prepared from bone marrow derived macrophages of 93 female and 114 male F(2) mice derived from a strain intercross between apoE-deficient mice on the AKR and DBA/2 genetic backgrounds, and was subjected to transcriptome profiling using microarrays. A high density genome scan was performed using a mouse SNP chip, and expression QTLs (eQTLs) were located for expressed transcripts. Using suggestive and significant LOD score cutoffs of 3.0 and 4.3, respectively, thousands of eQTLs in the female and male cohorts were identified. At the suggestive LOD threshold the majority of the eQTLs were trans eQTLs, mapping unlinked to the position of the gene. Cis eQTLs, which mapped to the location of the gene, had much higher LOD scores than trans eQTLs, indicating their more direct effect on gene expression. The majority of cis eQTLs were common to both males and females, but only approximately 1% of the trans eQTLs were shared by both sexes. At the significant LOD threshold, the majority of eQTLs were cis eQTLs, which were mostly sex-shared, while the trans eQTLs were overwhelmingly sex-specific. Pooling the male and female data, 31% of expressed transcripts were expressed at different levels in males vs. females after correction for multiple testing.
CONCLUSIONS/SIGNIFICANCE
These studies demonstrate a large sex effect on gene expression and trans regulation, under conditions where male and female derived cells were cultured ex vivo and thus without the influence of endogenous sex steroids. These data suggest that eQTL data from male and female mice should be analyzed separately, as many effects, such as trans regulation are sex specific.
Topics: Animals; Female; Gene Expression Regulation; Hybridization, Genetic; Lod Score; Macrophages; Male; Mice; Mice, Inbred C57BL; Quantitative Trait Loci; Sex Factors
PubMed: 18197246
DOI: 10.1371/journal.pone.0001435 -
The New England Journal of Medicine Oct 1990Marfan syndrome, "the founding member" of the heritable disorders of connective tissue, is a common autosomal dominant disorder with highly variable clinical...
BACKGROUND
Marfan syndrome, "the founding member" of the heritable disorders of connective tissue, is a common autosomal dominant disorder with highly variable clinical manifestations in the skeletal, ocular, and cardiovascular systems. The fundamental defect leading to this disease has escaped definition despite decades of research efforts by several groups of investigators.
METHODS AND RESULTS
Using linkage analyses with polymorphic markers of the human genome, we mapped the genetic defect to chromosome 15 in five families with Marfan syndrome. With three polymorphic markers we obtained definitive proof of linkage in these families (lod score = 3.92, theta = 0.0 +/- 0.11). The most probable location of the gene for the disease is currently D15S45 (lod score = 3.32, theta = 0.0 +/- 0.12).
CONCLUSIONS
The chromosomal localization of the mutation in Marfan syndrome is a first step toward the isolation and characterization of the defective gene and serves as a diagnostic test in families in which cosegregation of these markers with the disease has been confirmed.
Topics: Chromosome Mapping; Chromosomes, Human, Pair 15; Female; Humans; Lod Score; Male; Marfan Syndrome
PubMed: 2402262
DOI: 10.1056/NEJM199010043231402 -
Journal of Medical Genetics Feb 1990The combined genetic data between the Marfan syndrome and 75 informative loci on 18 autosomes were used to construct an exclusion map for this disorder. Data are also...
The combined genetic data between the Marfan syndrome and 75 informative loci on 18 autosomes were used to construct an exclusion map for this disorder. Data are also presented for a further two unmapped markers. The most likely location of the Marfan syndrome gene is highlighted and all the unexcluded areas of the genome are displayed in a graphical form. This exclusion map shows that almost 75% of the genome has been excluded as a likely location for the Marfan syndrome gene in the majority of the families studied. Apart from chromosomes 8, 13, 21, and 22, for which no data were available, other regions not excluded yet include 5p, 6p, 9p, 10p, 12p, 15, 17p, 18, and 20p. Future linkage analysis using markers located in the highlighted regions should facilitate the identification of the site of the Marfan syndrome gene.
Topics: Chromosome Mapping; Computers; Genetic Linkage; Genetic Markers; Humans; Lod Score; Marfan Syndrome
PubMed: 2319588
DOI: 10.1136/jmg.27.2.73 -
American Journal of Medical Genetics.... Mar 2006Susceptibility genes for Alzheimer's disease are proving to be highly challenging to detect and verify. Population heterogeneity may be a significant confounding factor...
Susceptibility genes for Alzheimer's disease are proving to be highly challenging to detect and verify. Population heterogeneity may be a significant confounding factor contributing to this difficulty. To increase the power for disease susceptibility gene detection, we conducted a genome-wide genetic linkage screen using individuals from the relatively isolated, genetically homogeneous, Amish population. Our genome linkage analysis used a 407-microsatellite-marker map (average density 7 cM) to search for autosomal genes linked to dementia in five Amish families from four Midwestern U.S. counties. Our highest two-point lod score (3.01) was observed at marker D4S1548 on chromosome 4q31. Five other regions (10q22, 3q28, 11p13, 4q28, 19p13) also demonstrated suggestive linkage with markers having two-point lod scores >2.0. While two of these regions are novel (4q31 and 11p13), the other regions lie close to regions identified in previous genome scans in other populations. Our results identify regions of the genome that may harbor genes involved in a subset of dementia patients, in particular the North American Amish community.
Topics: Dementia; Ethnicity; Female; Genetic Linkage; Genome, Human; Genotype; Humans; Indiana; Lod Score; Male; Microsatellite Repeats; Ohio
PubMed: 16389594
DOI: 10.1002/ajmg.b.30257 -
Zhongguo Dang Dai Er Ke Za Zhi =... Feb 2010The present study performed linkage analysis and gene mapping to find the possible chromosome locus harboring in one family with benign familial infantile convulsions...
OBJECTIVE
The present study performed linkage analysis and gene mapping to find the possible chromosome locus harboring in one family with benign familial infantile convulsions (BFIC) and investigate the possible molecular pathogenesis of BFIC.
METHODS
A four-generation family with BFIC was investigated. The family was genotyped using eight hypervariable microsatellite markers covering four loci: D19S245 and D19S250 for the 19q12-13.1 region, D16S3131 and D16S3133 for the 16p12-q12 region, D2S156 and D2S286 for the 2q24 region, and D20S480 and D20S481 for the 20q13.3 region. Polymorphism fragments were amplified using polymerase chain reaction (PCR) method. PCR products for the markers were subjected to electrophoresis on 8% denatured polyacrylamide gel and silver staining for length judgment of amplification fragment. Linkage analysis was performed by use of MLINK in the LINKAGE computer package. Two-point LOD scores were calculated to estimate the linkage relationship.
RESULTS
The two-point LOD scores were less than -2.0 for the genetic markers at chromosomes 19q12-13.1, 16p12-q12 and 2q24 at the recombination rate between 0.000 and 0.01. The two-point LOD scores for D20S481 at the 20q13.3 region were 0.3 and 0.25 at the recombination rate of 0.000 and 0.01, respectively.
CONCLUSIONS
There is no evidence that this family with BFIC is linked to one of the following loci: 19q12-13.1, 16p12-q12 and 2q24, but a possible linkage with 20q13.3 region cannot be excluded.
Topics: Chromosome Mapping; Epilepsy, Benign Neonatal; Female; Genetic Linkage; Humans; Lod Score; Male; Microsatellite Repeats
PubMed: 20199718
DOI: No ID Found