Multipoint LOD Score Research Articles

P1-361: Mapping genes affecting age-at-onset of Alzheimer’s disease in the chromosome 8

Identification of genes that affect age–at–onset (AAO) of AD has a profound impact in understanding the genetics of AD, and will potentially improve prevention and treatment in this aging–related neurodegenerative disorder. We previously conducted a whole genome screen for AAO of AD using 449 families and identified several linkage regions including chromosome 8q. The linkage region of chromosome 8q covers 46cM interval (between 119 to 165cM; LOD>1.0) with a peak multipoint LOD score of 2.09. To further map the gene(s) that is responsible for the LOD peak in this region of the chromosome 8, using variance–component procedure in SOLAR with increased sample size, and using Illumina Goldengate genotyping method. We genotyped four micro–satellite markers under this linkage region using additional 158 families with the same linkage analysis as in our previous study. We then followed up a 1–LOD score down region from the linkage peak using high density SNPs by genotyping 1536 Illumina Goldengate SNPs for association study to fine map the region. We obtained an updated two–point LOD score of 2.34 at the marker D8S1179. In addition, the new analysis narrowed the peak region to about 20cM (between 128 to149cM; LOD>1.0). We are currently genotyping 1536 Illumina Goldengate SNP OPA to follow up the ∼24mb area between q23.3 to q24.23 in Chr8 under the new linkage peak. These data strengthen the evidence for a potential gene(s) in this region contributing to the genetic etiology of AAO in AD.

Familial Osteoarthritis of the Hip Joint Associated with Acetabular Dysplasia Maps to Chromosome 13q

Genetic factors have been implicated in osteoarthritis (OA), particularly in OA of the hip joint (hip OA). Several instances of familial hip OA that show distinctive modes of inheritance but that differ from chondrodysplasia have been reported. Here, we report the characterization of a large Japanese family with an inherited disease of the hip that is indistinguishable from common hip OA, as evidenced by clinical symptoms and radiographs of the joint. This family contained eight patients in 4 generations. Affected individuals develop pain in the hip joint during adolescence, and the disease progresses to severe crippling before age 60 years. Patients generally are in good health, height is not reduced, and there is no extraskeletal involvement suggestive of chondrodysplasia. The skeletal change is bilateral acetabular dysplasia followed by OA, which occurs after age approximately 40 years and is indistinguishable from idiopathic nonfamilial dysplastic hip OA. This trait shows autosomal dominant inheritance, with a considerably consistent phenotype. Genomewide screening revealed linkage at chromosome 13q22, and haplotype analysis narrowed the locus to a 6.0-cM interval between markers D13S1296 and D13S162, with a maximal multipoint LOD score of 3.57. The family described here represents a novel genetic entity as a monogenic form of hip OA. Its further characterization can aid in elucidating the etiology and pathogenesis of a common idiopathic form of OA.

Genome-wide linkage scan for loci influencing plasma triglycerides

Background Plasma triglyceride concentration is known to be a significant risk factor for cardiovascular disease (CVD). Previous studies have found that the level of triglycerides is strongly influenced by genetic factors. Methods To identify quantitative trait loci influencing triglycerides, we conducted a genome-wide linkage scan on data from 485 Australian adult dizygotic twin pairs. Prior to linkage analysis, triglyceride values were adjusted for the effects of covariates including age, sex, time since last meal, time of blood collection (CT) and time to plasma separation. Results The heritability estimate for ln(triglyceride) adjusted for all above fixed effects was 0.49. The highest multipoint LOD score observed was 2.94 (genome-wide p = 0.049) on chromosome 7 (at 65 cM). This 7p region contains several candidate genes. Two other regions with suggestive multipoint LOD scores were also identified on chromosome 4 (LOD score = 2.26 at 62 cM) and chromosome X (LOD score = 2.01 at 81 cM). Conclusions The linkage peaks found represent newly identified regions for more detailed study, in particular the significant linkage observed on chromosome 7p13.

Online System for Faster Multipoint Linkage Analysis via Parallel Execution on Thousands of Personal Computers

Computation of LOD scores is a valuable tool for mapping disease-susceptibility genes in the study of Mendelian and complex diseases. However, computation of exact multipoint likelihoods of large inbred pedigrees with extensive missing data is often beyond the capabilities of a single computer. We present a distributed system called "SUPERLINK-ONLINE," for the computation of multipoint LOD scores of large inbred pedigrees. It achieves high performance via the efficient parallelization of the algorithms in SUPERLINK, a state-of-the-art serial program for these tasks, and through the use of the idle cycles of thousands of personal computers. The main algorithmic challenge has been to efficiently split a large task for distributed execution in a highly dynamic, nondedicated running environment. Notably, the system is available online, which allows computationally intensive analyses to be performed with no need for either the installation of software or the maintenance of a complicated distributed environment. As the system was being developed, it was extensively tested by collaborating medical centers worldwide on a variety of real data sets, some of which are presented in this article.

DFNB68, a novel autosomal recessive non-syndromic hearing impairment locus at chromosomal region 19p13.2

From a large collection of families with autosomal recessive non-syndromic hearing impairment (NSHI) from Pakistan, linkage has been established for two unrelated consanguineous families to 19p13.2. This new locus was assigned the name DFNB68. A 10 cM genome scan and additional fine mapping were carried out using microsatellite marker loci. Linkage was established for both families to DFNB68 with maximum multipoint LOD scores of 4.8 and 4.6. The overlap of the homozygous regions between the two families was bounded by D19S586 and D19S584, which limits the locus interval to 1.9 cM and contains 1.4 Mb. The genes CTL2, KEAP1 and CDKN2D were screened but were negative for functional sequence variants.

Distribution and magnitude of type I error of model‐based multipoint lod scores: implications for multipoint mod scores

The multipoint lod score and mod score methods have been advocated for their superior power in detecting linkage. However, little has been done to determine the distribution of multipoint lod scores or to examine the properties of mod scores. In this paper we study the distribution of multipoint lod scores both analytically and by simulation. We also study by simulation the distribution of maximum multipoint lod scores when maximized over different penetrance models. The multipoint lod score is approximately normally distributed with mean and variance that depend on marker informativity, marker density, specified genetic model, number of pedigrees, pedigree structure, and pattern of affection status. When the multipoint lod scores are maximized over a set of assumed penetrances models, an excess of false positive indications of linkage appear under dominant analysis models with low penetrances and under recessive analysis models with high penetrances. Therefore, caution should be taken in interpreting results when employing multipoint lod score and mod score approaches, in particular when inferring the level of linkage significance and the mode of inheritance of a trait.

Localization of a novel autosomal recessive nonsyndromic hearing impairment locus DFNB65 to chromosome 20q13.2–q13.32

Autosomal recessive nonsyndromic hearing impairment (ARNSHI) is the most frequent form of prelingual hereditary hearing loss in humans. Between 75 and 80% of all nonsyndromic deafness is inherited in an autosomal recessive pattern. Using linkage analysis, we have mapped a novel gene responsible for this form of nonsyndromic hearing impairment, DFNB65, in a consanguineous family from the Azad Jammu and Kashmir regions, which border Pakistan and India. A maximum multipoint LOD score of 3.3 was obtained at marker D20S840. The three-unit support interval is contained between markers D20S902 and D20S430, while the region of homozygosity is flanked by markers D20S480 and D20S430. The novel locus maps to a 10.5-cM region on chromosome 20q13.2-q13.32 and corresponds to a physical map distance of 4.3 Mb. DFNB65 represents the first ARNSHI locus to map to chromosome 20.

Genetic heterogeneity of synpolydactyly: a novel locus SPD3 maps to chromosome 14q11.2‐q12

Syndactyly type II or synpolydactyly (SPD) is the second most frequent syndactyly type and is inherited in an autosomal dominant fashion. The cardinal features of this malformation are the cutaneous or bony fusion of third and fourth fingers, and fourth and fifth toes associated with additional digital elements within the web. It shows incomplete penetrance and high inter- and intrafamilial phenotypic variability. Two loci are known for SPD (MIM 186000, MIM 608180) associated with mutations in HOXD13 and FBLN1, respectively. Here, we report further genetic heterogeneity for SDP. Employing a whole genomic screen, we demonstrate, in a large Pakistani kindred, that the classical phenotype of SPD maps on a new locus at chromosome 14q11.2-q12. The highest LOD score (Z(max) = 4.06) was obtained with microsatellite marker D14S264, and the multipoint LOD score reached a maximum of 5.01. Haplotype analysis revealed that the disease interval is flanked by microsatellite markers D14S283 and D14S1060, encompassing a physical distance of 10.72 Mb. We propose to allocate to this locus the symbol SPD3 (synpolydactyly 3), and to name the loci associated with HOXD13 or FBLN1 mutations SPD1 and SPD2, respectively.

Linkage of autosomal-dominant common variable immunodeficiency to chromosome 4q

The phenotype of common variable immunodeficiency (CVID) is characterized by recurrent infections owing to hypogammaglobulinemia, with deficiency in immunoglobulin (Ig)G and at least one of IgA or IgM. Family studies have shown a genetic association between CVID and selective IgA deficiency (IgAD), the latter being a milder disorder compatible with normal health. Approximately 20-25% of CVID cases are familial, if one includes families with at least one case of CVID and one of IgAD. Nijenhuis et al described a five-generation family with six cases of CVID, five cases of IgAD, and three cases of dysgammaglobulinemia. We conducted a genome-wide scan on this family seeking genetic linkage. One interval on chromosome 4q gives a peak multipoint LOD score of 2.70 using a strict model that treats only the CVID patients and one obligate carrier with dysgammaglobulinemia as affected. Extending the definition of likely affected to include IgAD boosts the peak multipoint LOD score to 3.38. The linkage interval spans at least from D4S2361 to D4S1572. We extended our study to a collection of 32 families with at least one CVID case and a second case of either CVID or IgAD. We used the same dominant penetrance model and genotyped and analyzed nine markers on 4q. The 32 families have a peak multipoint LOD score under heterogeneity of 0.96 between markers D4S423 and D4S1572 within the suggested linkage interval of the first family, and an estimated proportion of linked families (alpha) of 0.32, supporting the existence of a disease-causing gene for autosomal-dominant CVID/IgAD on chromosome 4q.

A novel locus (RP33) for autosomal dominant retinitis pigmentosa mapping to chromosomal region 2cen-q12.1

Retinitis pigmentosa (RP) is a heterogeneous group of progressive degenerative disorders of the retina with a strong genetic component. Here, we report the clinical and genetic findings in a Chinese family in which autosomal dominant RP (adRP) was inherited by 13 affected members in four generations. Using a genome-wide linkage screening approach, a novel disease locus (RP33) was assigned to the long arm of chromosome 2. A maximum multi-point LOD score of 4.69 was reached at marker D2S2222 in 2q11.2. Meiotic recombination events in affected members placed RP33 in a 15.5 cM region between D2S329 and D2S2229. From meiotic recombinations in two unaffected members RP33 was further refined to a 4.8 cM (9.5 Mb) interval flanked by D2S2159 and D2S1343 in chromosomal region 2cen-q12.1. No disease-associated mutations were detected in the candidate genes SEMA4C, CNGA3 or HNK1ST from within the region. MERTK, a known disease gene for autosomal recessive RP located close to RP33 was similarly excluded. Clinically, the family presented relatively late onset of night blindness, gradually decreased visual acuity, progressive loss of peripheral visual field and typical RP fundus changes in the mid-periphery of the retina. In conclusion, a novel locus for adRP has been assigned to chromosomal region 2cen-q12.1, which in the present kindred was associated with a relatively late onset form of the disease.

Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3

The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive spasticity in the lower limbs. Twenty-nine different loci (SPG) have been mapped so far, and 11 responsible genes have been identified. Clinically, one distinguishes between pure and complex HSP forms which are variably associated with numerous combinations of neurological and extra-neurological signs. Less is known about autosomal recessive forms (ARHSP) since the mapped loci have been identified often in single families and account for only a small percentage of patients. We report a new ARHSP locus (SPG30) on chromosome 2q37.3 in a consanguineous family with seven unaffected and four affected members of Algerian origin living in Eastern France with a significant multipoint lod score of 3.8. Ten other families from France (n = 4), Tunisia (n = 2), Algeria (n = 3) and the Czech Republic (n = 1) were not linked to the newly identified locus thus demonstrating further genetic heterogeneity. The phenotype of the linked family consists of spastic paraparesis and peripheral neuropathy associated with slight cerebellar signs confirmed by cerebellar atrophy on one CT scan.

The mapping of DFNB62, a new locus for autosomal recessive non‐syndromic hearing impairment, to chromosome 12p13.2‐p11.23

Autosomal recessive non-syndromic hearing impairment (ARNSHI) is the most common form of prelingual inherited hearing impairment (HI). Here is described the mapping of a novel ARNSHI locus in a consanguineous Pakistani family with profound congenital HI. Two-point and multipoint linkage analyses were performed for the genome scan and fine mapping markers. Haplotypes were constructed to determine the region of homozygosity. At theta = 0, the maximum two-point LOD score of 4.0 was obtained at marker AAC040. A maximum multipoint LOD score of 5.3 was derived at marker D12S320, with the three-unit support interval demarcated by D12S89 and D12S1042. The region of homozygosity is flanked by markers D12S358 and D12S1042, which corresponds to 22.4 cM according to the Rutgers combined linkage-physical map of the human genome and spans 15.0 Mb on the sequence-based physical map. A novel ARNSHI locus DFNB62 was mapped to chromosome 12p13.2-p11.23. DFNB62 represents the second ARNSHI locus to map to chromosome 12.

A new phenotype linked to SPG27 and refinement of the critical region on chromosome

Hereditary spastic paraplegias are genetically and clinically heterogeneous. Twenty-six loci have been identified to date. SPG27 was recently mapped to chromosome 10 in a single family with autosomal recessive hereditary spastic paraplegia (AR-HSP) and a pure phenotype. We describe a Tunisian family with a complicated form of AR-HSP also linked to SPG27. The parents are first cousins and 3 out of their 4 children manifest early onset progressive spastic paraparesis associated with sensorimotor polyneuropathy. In addition, the eldest girl had facial dysmorphism and short stature (-3SD). Two of the three patients were mentally retarded, and one of these also had cerebellar signs. Their ages at onset were 2, 5 and 7 years. A genome-wide scan suggested linkage to SPG27 on the long arm of chromosome 10 with a multipoint lod score of 2.54. In addition, a recombination detected in this family by haplotype reconstruction reduced the SPG27 locus from 25 to 19.6 cM. This is the first clinical description of a complicated form of spastic paraplegia, characterized by great phenotypic variability among the sibs, associated with the SPG27 locus.

The Cluster Variation Method for Efficient Linkage Analysis on Extended Pedigrees

BackgroundComputing exact multipoint LOD scores for extended pedigrees rapidly becomes infeasible as the number of markers and untyped individuals increase. When markers are excluded from the computation, significant power may be lost. Therefore accurate approximate methods which take into account all markers are desirable.MethodsWe present a novel method for efficient estimation of LOD scores on extended pedigrees. Our approach is based on the Cluster Variation Method, which deterministically estimates likelihoods by performing exact computations on tractable subsets of variables (clusters) of a Bayesian network. First a distribution over inheritances on the marker loci is approximated with the Cluster Variation Method. Then this distribution is used to estimate the LOD score for each location of the trait locus.ResultsFirst we demonstrate that significant power may be lost if markers are ignored in the multi-point analysis. On a set of pedigrees where exact computation is possible we compare the estimates of the LOD scores obtained with our method to the exact LOD scores. Secondly, we compare our method to a state of the art MCMC sampler. When both methods are given equal computation time, our method is more efficient. Finally, we show that CVM scales to large problem instances.ConclusionWe conclude that the Cluster Variation Method is as accurate as MCMC and generally is more efficient. Our method is a promising alternative to approaches based on MCMC sampling.

Genomic screen for loci associated with tobacco usage in Mission Indians

BackgroundThe prevalence of tobacco usage in Native American adults and adolescents is higher than any other racial or ethnic group, yet biological risk and protective factors underlying tobacco use in this ethnic group remain unknown. A genome scan for loci associated with tobacco use phenotypes was performed with data collected from a community sample of Mission Indians residing in Southwest California.MethodsA structured diagnostic interview was used to define two tobacco use phenotypes: 1) any regular tobacco usage (smoked daily for one month or more) and 2) persistent tobacco usage (smoked at least 10 cigarettes a day for more than one year). Heritability was determined and a linkage analysis was performed, using genotypes for a panel 791 microsatellite polymorphisms, for the two phenotypes using variance component methods implemented in SOLAR.ResultsAnalyses of multipoint variance component LOD scores for the two tobacco use phenotypes revealed two scores that exceeded 2.0 for the regular use phenotype: one on chromosomes 6 and one on 8. Four other loci on chromosomes 1,7,13, and 22 were found with LOD scores between 1.0 and 1.5. Two loci of interest were found on chromosomes 1 and 4 for the persistent use phenotype with LOD scores between 1.3–1.5. Bivariate linkage analysis was conducted at the site on chromosome 4 for persistent tobacco use and an alcohol drinking severity phenotype previously identified at this site. The maximum LOD score for the bivariate analysis for the region was 3.4, however, there was insufficient power to exclude coincident linkage.ConclusionWhile not providing evidence for linkage to specific chromosomal regions these results identify regions of interest in the genome in this Mission Indian population, for tobacco usage, some of which were identified in previous genome scans of non-native populations. Additionally, these data lend support for the hypothesis that cigarette smoking, alcohol dependence and other consumptive behaviors may share some common risk and/or protective factors in this Mission Indian population.

A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia

To perform genetic linkage analysis in a family affected with ALS and frontotemporal dementia (FTD). The authors performed a genome-wide linkage analysis of a four-generation, 50-member Scandinavian family in which five individuals were diagnosed with ALS and nine with FTD. Linkage calculations assuming autosomal dominant inheritance of a single neurodegenerative disease manifesting as either ALS or FTD with age-dependent penetrance were performed. Further analyses for ALS alone and FTD alone were performed. A parametric logarithm of odds (lod) score of 2.0 or greater was required for further study of a potential locus and crossover (haplotype) analysis. A new ALS-FTD locus was identified between markers D9s1870 and D9s1791 on human chromosome 9p21.3-p13.3. A maximum multipoint lod score of 3.00 was obtained between markers D9s1121 and D9s2154. Crossover analysis indicates this region covers approximately 21.8 cM, or 14Mb. A locus on chromosome 9p21.3-p13.3 is linked to ALS-FTD.

A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17

Over 30 different mutations have now been identified in MAPt that cause frontotemporal dementia (FTD). However, there are several families with FTD that show definite linkage to the region on chromosome 17 that contains MAPt, in which no mutation(s) has been identified. Although these families could have a complex mutation of the MAPt locus that has evaded detection it is also possible that another gene in this region is associated with FTD. This possibility is supported by neuropathological findings in these families, which consist of neuronal inclusions that are immunoreactive for ubiquitin (ub-ir) but not for tau. In addition to neuronal cytoplasmic inclusions, several chromosome 17-linked families are reported to have ub-ir neuronal intranuclear inclusions (NII); a finding which is uncommon in sporadic FTD. Here, we describe detailed clinical and neuropathological findings in a new large, multigenerational family with autosomal dominant FTD and autopsy proven tau-negative, ub-ir neuronal cytoplasmic and intranuclear inclusions. We have demonstrated that this family is linked to a 19.06 cM region of chromosome 17q21 with a maximum multipoint LOD score of 3.911 containing MAPt. By combining the results of our genetic analysis with those previously published for other families with similar pathology, we have further refined the minimal region to a 3.53 cM region of chromosome 17q21. We did not identify point mutations in MAPt by direct sequencing or any gross MAPt gene alterations using fluorescent in situ hybridization. In addition, tau protein extracted from members of this family was unremarkable in size and quantity as assessed by western blotting. Neuropathological characterization of the ub-ir NII in this family shows that they are positive for promyelocytic leukaemia protein (PML) and SUMO-1 that suggests that these inclusions form in the nuclear body and suggests a possible mechanism of neurodegeneration in tau-negative FTD linked to chromosome 17q21.

Use of LINKAGE Programs for Linkage Analysis

Genetic linkage analysis remains a powerful tool for identifying regions of the genome that may harbor suceptibility loci. This unit describes the traditional approach of calculating two-point and multipoint lod scores when the underlying genetic model is known. Components of the genetic model include whether a trait is dominant, recessive, or codominant, whether it is autosomal or sex linked, and whether there is mutation at the disease gene locus, as well as the disease and marker allele frequencies and the penetrance of the disease allele. The approach to genetic linkage analysis presented in this unit assumes that the markers are loosely spaced, so that there is no linkage disequilibrium between genetic markers. Practical examples and step-by-step guidelines are presented.

A Locus on Chromosome 13 Influences Levels of TAFI Antigen in Healthy Mexican Americans

When activated, thrombin activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis by modifying fibrin, depressing its plasminogen binding potential. Polymorphisms in the TAFI structural gene (CPB2) have been associated with variation in TAFI levels, but the potential occurrence of influential quantitative trait loci (QTLs) located elsewhere in the genome has been explored only in families ascertained in part through probands affected by thrombosis. We report the results of the first genome-wide linkage screen for QTLs that influence TAFI phenotypes. Data are from 635 subjects from 21 randomly ascertained Mexican American families participating in the San Antonio Family Heart Study. Potential QTLs were localized through a genome-wide multipoint linkage scan using 417 highly informative autosomal short tandem repeat markers spaced at approximately 10-cM intervals. We observed a maximum multipoint LOD score of 3.09 on chromosome 13q, the region of the TAFI structural gene. A suggestive linkage signal (LOD = 2.04) also was observed in this region, but may be an artifact. In addition, weak evidence for linkage occurred on chromosomes 17p and 9q. Our results suggest that polymorphisms in the TAFI structural gene or its nearby regulatory elements may contribute strongly to TAFI level variation in the general population, although several genes in other regions of the genome may also influence variation in this phenotype. Our findings support those of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project, which identified a potential TAFI QTL on chromosome 13q in a genome-wide linkage scan in Spanish thrombophilia families.

Two novel quantitative trait linkage analysis statistics based on the posterior probability of linkage: application to the COGA families

BackgroundIn this paper we apply two novel quantitative trait linkage statistics based on the posterior probability of linkage (PPL) to chromosome 4 from the GAW 14 COGA dataset. Our approaches are advantageous since they use the full likelihood, use full phenotypic information, do not assume normality at the population level or require population/sample parameter estimates; and like other forms of the PPL, they are specifically tailored to accumulate linkage evidence, either for or against linkage, across multiple sets of heterogeneous data.ResultsThe first statistic uses all quantitative trait (QT) information from the pedigree (QT-posterior probability of linkage, PPL); we applied the QT-PPL to the trait ecb21 (resting electroencephalogram). The second statistic allows simultaneous incorporation of dichotomous trait data into the QT analysis via a threshold model (QTT-PPL); we applied the QTT-PPL to combined data on ecb21 and ALDX1. We obtained a QT-PPL of 96% at GABRB1 and a QT-PPL of 18% at FABP2 while the QTT-PPL was 4% and 2% at the same two loci, respectively. By comparison, the variance-components (VC) method, as implemented in SOLAR, yielded multipoint VC LOD scores of 2.05 and 2.21 at GABRB1 and FABP2, respectively; no other VC LODs were greater than 2.ConclusionThe QTT-PPL was only 4% at GABARB1, which might suggest that the underlying ecb21 gene does not also cause ALDX1, although features of the data complicate interpretation of this result.