-
G3 (Bethesda, Md.) Jul 2019The high mapping resolution of multiparental populations, combined with technology to measure tens of thousands of phenotypes, presents a need for quantitative methods...
The high mapping resolution of multiparental populations, combined with technology to measure tens of thousands of phenotypes, presents a need for quantitative methods to enhance understanding of the genetic architecture of complex traits. When multiple traits map to a common genomic region, knowledge of the number of distinct loci provides important insight into the underlying mechanism and can assist planning for subsequent experiments. We extend the method of Jiang and Zeng (1995), for testing pleiotropy with a pair of traits, to the case of more than two alleles. We also incorporate polygenic random effects to account for population structure. We use a parametric bootstrap to determine statistical significance. We apply our methods to a behavioral genetics data set from Diversity Outbred mice. Our methods have been incorporated into the R package qtl2pleio.
Topics: Algorithms; Computer Simulation; Crosses, Genetic; Genetic Pleiotropy; Genetics, Population; Lod Score; Models, Genetic; Multifactorial Inheritance; Quantitative Trait Loci
PubMed: 31092608
DOI: 10.1534/g3.119.400098 -
Human Heredity 2012We present a parametric method for linkage analysis of quantitative phenotypes. The method provides a test for linkage as well as an estimate of different phenotype...
OBJECTIVE
We present a parametric method for linkage analysis of quantitative phenotypes. The method provides a test for linkage as well as an estimate of different phenotype parameters. We have implemented our new method in the program GENEHUNTER-QMOD and evaluated its properties by performing simulations.
METHODS
The phenotype is modeled as a normally distributed variable, with a separate distribution for each genotype. Parameter estimates are obtained by maximizing the LOD score over the normal distribution parameters with a gradient-based optimization called PGRAD method.
RESULTS
The PGRAD method has lower power to detect linkage than the variance components analysis (VCA) in case of a normal distribution and small pedigrees. However, it outperforms the VCA and Haseman-Elston regression for extended pedigrees, nonrandomly ascertained data and non-normally distributed phenotypes. Here, the higher power even goes along with conservativeness, while the VCA has an inflated type I error. Parameter estimation tends to underestimate residual variances but performs better for expectation values of the phenotype distributions.
CONCLUSION
With GENEHUNTER-QMOD, a powerful new tool is provided to explicitly model quantitative phenotypes in the context of linkage analysis. It is freely available at http://www.helmholtz-muenchen.de/genepi/downloads.
Topics: Algorithms; Alleles; Chromosome Mapping; Computational Biology; Computer Simulation; Genetic Linkage; Genetic Predisposition to Disease; Genetics, Population; Humans; Lod Score; Models, Genetic; Pedigree; Phenotype; Quantitative Trait Loci; Software
PubMed: 22948723
DOI: 10.1159/000339904 -
American Journal of Human Genetics Mar 2004We recently reported a two-stage genomewide screen of 48 sib pairs affected with intracranial aneurysms (IAs) that revealed suggestive linkage to chromosome 19q13, with...
We recently reported a two-stage genomewide screen of 48 sib pairs affected with intracranial aneurysms (IAs) that revealed suggestive linkage to chromosome 19q13, with a LOD score of 2.58. The region supporting linkage spanned approximately 22 cM. Here, we report a follow-up study of the locus at 19q13, with a sample size expanded to 139 affected sib pairs, along with 83 other affected relative pairs (222 affected relative pairs in total). Suggestive linkage was observed in both independent sample sets, and linkage was significant in the combined set at 70 cM (LOD score 3.50; P=.00006) and at 80 cM (LOD score 3.93; P=.00002). Linkage was highly significant at 70 cM (LOD score 5.70; P=.000001) and at 80 cM (LOD score 3.99; P=.00005) when a covariate measuring the number of affected individuals in the nuclear family was included. To evaluate further the contribution to the linkage signal from families with more than two affected relatives, we performed model-based linkage analysis with a recessive model and a range of penetrances, and we obtained maximum linkage at 70 cM (LOD score 3.16; P=.00007) with a penetrance of 0.3. We then estimated location by using GENEFINDER. The most likely location for a gene predisposing to IAs in the Finnish population is in a region with a 95% confidence interval of 11.6 cM (P=.00007) centered 2.0 cM proximal to D19S246.
Topics: Chromosomes, Human, Pair 19; Female; Finland; Genetic Linkage; Genetic Markers; Genetic Predisposition to Disease; Humans; Intracranial Aneurysm; Lod Score; Male; Microsatellite Repeats
PubMed: 14872410
DOI: 10.1086/382285 -
Genetics and Molecular Research : GMR Jun 2015Capsicum baccatum L. is one of the five Capsicum domesticated species and has multiple uses in the food, pharmaceutical and cosmetic industries. This species is also a...
Capsicum baccatum L. is one of the five Capsicum domesticated species and has multiple uses in the food, pharmaceutical and cosmetic industries. This species is also a valuable source of genes for chili pepper breeding, especially genes for disease resistance and fruit quality. However, knowledge of the genetic structure of C. baccatum is limited. A reference map for C. baccatum (2n = 2x = 24) based on 42 microsatellite, 85 inter-simple sequence repeat, and 56 random amplified polymorphic DNA markers was constructed using an F2 population consisting of 203 individuals. The map was generated using the JoinMap software (version 4.0) and the linkage groups were formed and ordered using a LOD score of 3.0 and maximum of 40% recombination. The genetic map consisted of 12 major and four minor linkage groups covering a total genome distance of 2547.5 cM with an average distance of 14.25 cM between markers. Of the 152 pairs of microsatellite markers available for Capsicum annuum, 62 were successfully transferred to C. baccatum, generating polymorphism. Forty-two of these markers were mapped, allowing the introduction of C. baccatum in synteny studies with other species of the genus Capsicum.
Topics: Alleles; Capsicum; Chromosome Mapping; Genetic Markers; Genome, Plant; Lod Score; Microsatellite Repeats; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Quantitative Trait Loci
PubMed: 26125877
DOI: 10.4238/2015.June.18.12 -
Nature Communications Jul 2020As the number of genomics datasets grows rapidly, sample mislabeling has become a high stakes issue. We present CrosscheckFingerprints (Crosscheck), a tool for...
As the number of genomics datasets grows rapidly, sample mislabeling has become a high stakes issue. We present CrosscheckFingerprints (Crosscheck), a tool for quantifying sample-relatedness and detecting incorrectly paired sequencing datasets from different donors. Crosscheck outperforms similar methods and is effective even when data are sparse or from different assays. Application of Crosscheck to 8851 ENCODE ChIP-, RNA-, and DNase-seq datasets enabled us to identify and correct dozens of mislabeled samples and ambiguous metadata annotations, representing ~1% of ENCODE datasets.
Topics: Databases, Nucleic Acid; Genotype; HEK293 Cells; High-Throughput Nucleotide Sequencing; Human Umbilical Vein Endothelial Cells; Humans; K562 Cells; Linkage Disequilibrium; Lod Score; Molecular Sequence Annotation
PubMed: 32728101
DOI: 10.1038/s41467-020-17453-5 -
Molecular Psychiatry Oct 2010Genetic studies of autism over the past decade suggest a complex landscape of multiple genes. In the face of this heterogeneity, studies that include large extended...
Genetic studies of autism over the past decade suggest a complex landscape of multiple genes. In the face of this heterogeneity, studies that include large extended pedigrees may offer valuable insights, as the relatively few susceptibility genes within single large families may be more easily discerned. This genome-wide screen of 70 families includes 20 large extended pedigrees of 6-9 generations, 6 moderate-sized families of 4-5 generations and 44 smaller families of 2-3 generations. The Center for Inherited Disease Research (CIDR) provided genotyping using the Illumina Linkage Panel 12, a 6K single-nucleotide polymorphism (SNP) platform. Results from 192 subjects with an autism spectrum disorder (ASD) and 461 of their relatives revealed genome-wide significance on chromosome 15q, with three possibly distinct peaks: 15q13.1-q14 (heterogeneity LOD (HLOD)=4.09 at 29 459 872 bp); 15q14-q21.1 (HLOD=3.59 at 36 837 208 bp); and 15q21.1-q22.2 (HLOD=5.31 at 55 629 733 bp). Two of these peaks replicate earlier findings. There were additional suggestive results on chromosomes 2p25.3-p24.1 (HLOD=1.87), 7q31.31-q32.3 (HLOD=1.97) and 13q12.11-q12.3 (HLOD=1.93). Affected subjects in families supporting the linkage peaks found in this study did not reveal strong evidence for distinct phenotypic subgroups.
Topics: Adolescent; Autistic Disorder; Child; Chromosomes, Human, Pair 15; Female; Genetic Heterogeneity; Genetic Linkage; Genome-Wide Association Study; Genotype; Humans; Lod Score; Male; Pedigree; Phenotype; Utah
PubMed: 19455147
DOI: 10.1038/mp.2009.42 -
American Journal of Human Genetics May 2000When the mode of inheritance of a disease is unknown, the LOD-score method of linkage analysis must take into account uncertainties in model parameters. We have... (Comparative Study)
Comparative Study
When the mode of inheritance of a disease is unknown, the LOD-score method of linkage analysis must take into account uncertainties in model parameters. We have previously proposed a parametric linkage test called "MFLOD," which does not require specification of disease model parameters. In the present study, we introduce two new model-free parametric linkage tests, known as "MLOD" and "MALOD." These tests are defined, respectively, as the LOD score and the admixture LOD score, maximized (subject to the same constraints as MFLOD) over disease-model parameters. We compared the power of these three parametric linkage tests and that of two nonparametric linkage tests, NPLall and NPLpairs, which are implemented in GENEHUNTER. With the use of small pedigrees and a fully informative marker, we found the powers of MLOD, NPLall, and NPLpairs to be almost equivalent to each other and not far below that of a LOD-score analysis performed under the assumption the correct genetic parameters. Thus, linkage analysis is not much hindered by uncertain mode of inheritance. The results also suggest that both parametric and nonparametric methods are suitable for linkage analysis of complex disorders in small pedigrees. However, whether these results apply to large pedigrees remains to be answered.
Topics: Chromosome Mapping; Computer Simulation; Female; Genetic Diseases, Inborn; Genetic Markers; Humans; Lod Score; Male; Models, Genetic; Pedigree; Reproducibility of Results; Sample Size; Software; Statistics, Nonparametric
PubMed: 10762550
DOI: 10.1086/302888 -
The Journal of Investigative Dermatology Jun 2008Ichthyosis vulgaris (IV) is one of the most commonly inherited disorders and has an estimated prevalence rate of 2.29% in China. To date, only one gene responsible for...
Ichthyosis vulgaris (IV) is one of the most commonly inherited disorders and has an estimated prevalence rate of 2.29% in China. To date, only one gene responsible for IV, the filaggrin gene (FLG), was identified, but genetic heterogeneity exists. In this study, two Chinese families with autosomal-dominant IV were genetically characterized. The FLG gene was first excluded as the disease-causing gene in the two families. The larger family was then characterized by genome-wide linkage analysis to identify a new genetic locus for IV. Significant linkage was identified with markers on chromosome 10q22.3-q24.2 with a maximum LOD score of 3.19. No other markers showed a LOD score of >1.5. Fine mapping defined the new genetic locus within a 20.7 cM region between markers D10S569 and D10S1709. The second family also showed positive linkage to the same 10q22.3-q24.2 region. The combined maximum LOD score in the two families was 3.95. Identification of linkage in two independent families provides strong genetic evidence that a previously unreported gene for IV is located on chromosome 10q22.3-q24.2. Future studies of the candidate genes at the 10q IV locus will identify a specific gene, which will provide insights into the pathogenesis of IV.
Topics: China; Chromosome Mapping; Chromosomes, Human, Pair 10; Family Health; Female; Filaggrin Proteins; Genetic Linkage; Genetic Markers; Genetic Predisposition to Disease; Humans; Ichthyosis Vulgaris; Lod Score; Male; Models, Genetic; Pedigree; Recombination, Genetic
PubMed: 18079749
DOI: 10.1038/sj.jid.5701191 -
American Journal of Human Genetics Aug 2004Avascular necrosis of the femoral head (ANFH) is a debilitating disease that commonly leads to destruction of the hip joint in adults. The etiology of ANFH is unknown,...
Avascular necrosis of the femoral head (ANFH) is a debilitating disease that commonly leads to destruction of the hip joint in adults. The etiology of ANFH is unknown, but previous studies have indicated that heritable thrombophilia (increased tendency to form thrombi) and hypofibrinolysis (reduced ability to lyse thrombi), alcohol intake, and steroid use are risk factors for ANFH. We recently identified two families with ANFH showing autosomal dominant inheritance. By applying linkage analysis to a four-generation pedigree, we excluded linkage between the family and three genes related to thrombophilia and hypofibrinolysis: protein C, protein S, and plasminogen activator inhibitor. Furthermore, by a genomewide scan, a significant two-point LOD score of 3.45 (recombination fraction [theta] = 0) was obtained between the family with ANFH and marker D12S85 on chromosome 12. High-resolution mapping was conducted in a second family with ANFH and replicated the linkage to D12S368 (pedigree I: LOD score 2.47, theta = 0.05; pedigree II: LOD score 2.81, theta = 0.10). When an age-dependent-penetrance model was applied, the combined multipoint LOD score was 6.43 between D12S1663 and D12S85. Thus, we mapped the candidate gene for autosomal dominant ANFH to a 15-cM region between D12S1663 and D12S1632 on chromosome 12q13.
Topics: Adolescent; Adult; Child; Chromosome Mapping; Chromosomes, Human, Pair 12; Female; Femur Head Necrosis; Genes, Dominant; Genetic Linkage; Humans; Lod Score; Male; Pedigree; Taiwan
PubMed: 15179599
DOI: 10.1086/422702 -
PloS One 2023Next-generation sequencing has led to an explosion of genetic findings for many rare diseases. However, most of the variants identified are very rare and were also...
Next-generation sequencing has led to an explosion of genetic findings for many rare diseases. However, most of the variants identified are very rare and were also identified in small pedigrees, which creates challenges in terms of penetrance estimation and translation into genetic counselling in the setting of cascade testing. We use simulations to show that for a rare (dominant) disorder where a variant is identified in a small number of small pedigrees, the penetrance estimate can both have large uncertainty and be drastically inflated, due to underlying ascertainment bias. We have developed PenEst, an app that allows users to investigate the phenomenon across ranges of parameter settings. We also illustrate robust ascertainment corrections via the LOD (logarithm of the odds) score, and recommend a LOD-based approach to assessing pathogenicity of rare variants in the presence of reduced penetrance.
Topics: Genetic Counseling; Penetrance; Virulence; High-Throughput Nucleotide Sequencing; Lod Score
PubMed: 37733810
DOI: 10.1371/journal.pone.0290336