LINKAGE Package Research Articles

Genetic analysis of a large Han Chinese family line with schizoaffective psychosis

To locate the specific susceptibility genes of a high incidence of schizoaffective disease (SAD) with autonomic dominant inheritance, we recruited a family group from Henan Province with a high incidence of SAD, including 19 individuals sampled from five generations.We used a genome-wide high-density SNP chip to perform genotype detection. The LINKAGE package and MENDEL programs were used for. The two-point and multipoint analyses were calculated by Merlin and SimWalk2 software to obtain the nonparametric linkage (NPL) value, corresponding P value, and parameter linkage limit of detection (LOD) value.Genome-wide linkage analysis yielded a significant linkage signal located on the short arm of chromosome 19. In the dominant genetic model, the LOD of the multipoint parametric analysis was 2.5, and the nonparametric analysis was 19.4 (P < 0.00001). Further haploid genotype analysis localized the candidate region in the 19p13.3–13.2 region, beginning at rs178414 and ending at rs11668751 with a physical length of approximately 4.9 Mb. We believe that the genes responsible for SAD are in this region.

Reclin2: a Toolkit for Record Linkage and Deduplication

The goal of record linkage and deduplication is to detect which records belong to the same object in data sets where the identifiers of the objects contain errors and missing values. The main design considerations of reclin2 are: modularity/flexibility, speed and the ability to handle large data sets. The first points makes it easy for users to extend the package with custom process steps. This flexibility is obtained by using simple data structures and by following as close as possible common interfaces in R. For large problems it is possible to distribute the work over multiple worker nodes. A benchmark comparison to other record linkage packages for R, shows that for this specific benchmark, the fastLink package performs best. However, this package only performs one specific type of record linkage model. The performance of reclin2 is not far behind the of fastLink while allowing for much greater flexibility.

Closer to reality? The application of sequence analysis in crime linkage

PurposeTraditional crime linkage studies on serial sexual assaults have relied predominantly on a binary crime linkage approach that has yielded successful results in terms of linkage accuracy. Such an approach is a coarse reflection of reality by focussing mainly on the outcome of an offence, neglecting the forceful differences due to the intricate offender-victim interaction. Only few researchers have examined sexual assaults through the lens of a sequence analysis framework. This paper aims to present the first empirical test of offence sequence-based crime linkage, moving beyond exploratory analyses.Design/methodology/approachOffence accounts from 90 serial sexual assault and rape victims from the UK were analysed and sequentially coded. Sequence analysis allowed to compare all offences combinations regarding their underlying sequence of events. The resulting comparison was transformed and plotted in two-dimensional space by multidimensional scaling analysis for a visual inspection of linkage potential. The transformed proximities of all offences were used as predictors in a receiver operating characteristic analysis to actually test their discriminatory accuracy for crime linkage purpose.FindingsSequence analysis shows significant discriminatory accuracy for crime linkage purpose. However, the method does perform less well than previous binary crime linkage studies.Research limitations/implicationsSeveral limitations due to the nature of the data will be discussed.Practical implicationsThe practical limitations are as follows: the study is a potential practical value for crime analysts; it is a complimentary methodology for statistical crime linkage packages; it requires automated coding to be useful; and it is very dependent on crime recoding standards.Originality/valueThe exploratory part of this study has been published in a book chapter in 2015. However, to the best of the authors’ knowledge, the succinct test of crime linkage accuracy is the first of its kind.

Assembly of the LongSHOT cohort: public record linkage on a grand scale

BackgroundVirtually all existing evidence linking access to firearms to elevated risks of mortality and morbidity comes from ecological and case–control studies. To improve understanding of the health risks and benefits...

Technical challenges of providing record linkage services for research

BackgroundRecord linkage techniques are widely used to enable health researchers to gain event based longitudinal information for entire populations. The task of record linkage is increasingly being undertaken by specialised linkage units (SLUs). In addition to the complexity of undertaking probabilistic record linkage, these units face additional technical challenges in providing record linkage ‘as a service’ for research. The extent of this functionality, and approaches to solving these issues, has had little focus in the record linkage literature. Few, if any, of the record linkage packages or systems currently used by SLUs include the full range of functions required.MethodsThis paper identifies and discusses some of the functions that are required or undertaken by SLUs in the provision of record linkage services. These include managing routine, on-going linkage; storing and handling changing data; handling different linkage scenarios; accommodating ever increasing datasets. Automated linkage processes are one way of ensuring consistency of results and scalability of service.ResultsAlternative solutions to some of these challenges are presented. By maintaining a full history of links, and storing pairwise information, many of the challenges around handling ‘open’ records, and providing automated managed extractions are solved. A number of these solutions were implemented as part of the development of the National Linkage System (NLS) by the Centre for Data Linkage (part of the Population Health Research Network) in Australia.ConclusionsThe demand for, and complexity of, linkage services is growing. This presents as a challenge to SLUs as they seek to service the varying needs of dozens of research projects annually. Linkage units need to be both flexible and scalable to meet this demand. It is hoped the solutions presented here can help mitigate these difficulties.

U.S. Free Trade Agreements and Linkages

Abstract This article examines the driving factors that account for patterns of linkages to broader economic, labor, environmental, and security issues in U.S. Free Trade Agreements (FTAs). Rather than only emphasizing trade benefits or security considerations as in much recent work on FTAs, this analysis provides a richer empirical picture by focusing on the full universe of U.S. FTAs. It conceptually differentiates among different issues that might be linked to FTAs and categorizes different patterns of U.S. FTAs based on the key issues that drove negotiations. The article then examines these negotiations from a theoretical standpoint, focusing on three elements. First, it examines the degree to which linkages in the U.S. domestic policymaking process are top-down or bottom-up. Second, it considers linkages types in terms of the underlying basis for issue connections – either power or knowledge. Third, it more briefly examines the bargaining process. The conceptual and theoretical analysis is buttressed through an examination of various illustrative cases of U.S. FTA negotiations to demonstrate the utility of this approach to illuminate the variety of ‘linkage packages’ that have driven U.S. FTAs. We conclude with the broader implications of linkages politics in FTAs.

Mucolipidosis in a Chinese family with compound heterozygous mutations at the GNPTAB gene

BackgroundMucopolysaccharidoses (MPS) are caused by the deficiency in the metabolism of one or more types of mucopolysaccharides or glycosaminoglycans (GAGs). Mucolipidoses (ML) are a group of genetic disorders in which both glycosaminoglycans (GAGs) and sphingolipids build up in the body. Both of MPS and ML belong to lysosomal storage diseases and show similar clinical manifestations. Distinction of these two types of diseases has not been always possible using conventional clinical diagnoses. Genetic test provides a definitive diagnosis for ML and MPS diseases. MethodsThe initial clinical diagnosis had suspected the proband as either MPS or ML. To verify the clinical diagnosis, linkage analysis was performed with a panel of microsatellite markers flanking 10 candidate genetic loci for mucopolysaccharidosis and 2 loci for mucolipidosis. Two-point logarithm of odds (lod) scores was calculated using Linkage Package 5.2 program. Direct DNA sequence analyses of GNPTAB in the family members were performed. ResultsBy using linkage and mutational analyses, we have identified that the family members contain compound heterozygous mutations of p.R364X and c.2715+1G>A in the GNPTAB gene. We determine the family as MLIII based on the DNA-test and clinical diagnoses. ConclusionOur study confirms the pathological relationship between the patients' genotype and phenotype in the clinical ML manifestation, and suggests that DNA-based diagnosis serves as a better way to define ML and MPS.

Association of chromosome 2q36.1–36.3 and autosomal dominant transmission in ankylosing spondylitis: results of genetic studies across generations of Han Chinese families

Background:Ankylosing spondylitis (AS) is a chronic, potentially crippling, spondyloarthropathy with strong genetic components affecting approximately 0.3% of the population. Its exact genetic mechanism and mode of transmission, however, remains obscure.Methods...

A genome‐wide linkage analysis approach to find disease‐causing gene of Inherited Intracranial Aneurysm

Intracranial aneurysms (IAs) is characterized by abnormal bulging of one of arteries in the brain. The disease is believed to be caused by many environmental and genetic factors. In an attempt to elucidate the genetic factor contributing the etiology of IAs, a genome‐wide linkage analysis was conducted to find the locus for the disease‐causing gene of IAs. By careful investigation of the inheritance pattern of 600 IA patients at either Chonbuk National University Hospital (Chonju, South Korea) or Hana Hospital (Ilsan, South Korea), we recruited 5 families inheriting IAs dominantly. Entire genomes of the families were genotyped at 10 cM interval using ABI Linkage Mapping Set. A parametric method for linkage analyses was employed for each markerand calculated two‐point using LINKAGE package (v5.1). A lod score maximum of Zmax = 3.034 at θ= 0.00 was obtained with marker D8S549 located on chromosome 8p22. And a maximum multipoint LOD score was 3.067 on the 8p22 locus. Our results clearly imply that IAs in Korea have a genetic locus in 8p22.

Autosomal linkage analysis for cannabis use behaviors in Australian adults

Cannabis is the most commonly used illicit drug in developed and in developing nations. Twin studies have highlighted the role of genetic influences on early stages of cannabis use, such as a lifetime history of use, early-onset use and frequent use, however, we are not aware of any genomic studies that have examined these phenotypes. Using data on 2314 families consisting of 5600 adult Australian offspring and their parents, all of whom were scanned using 1399 unique autosomal markers, we conducted autosomal linkage analyses for lifetime history of cannabis initiation, early-onset cannabis use and frequency of use, using a variance components approach in the linkage package MERLIN. Suggestive evidence for linkage was found on chromosome 18 (LOD 2.14 for frequency of use, LOD 1.97 for initiation, at 90–97 cM) and also on chromosome 19 (LOD 1.92 for early-onset at 17 cM). These LOD scores did not meet genome-wide significance. Further replication of these linkage regions in other samples will be required, although these initial results suggest further targeted efforts on chromosome 18 may yield interesting candidate genes for early stages of cannabis-related behaviors.

A new candidate locus for bilateral perisylvian polymicrogyria mapped on chromosome Xq27

Polymicrogyria (PMG) is characterized by an excessive number of small and prominent brain gyri, separated by shallow sulci. Bilateral perisylvian polymicrogyria (BPP) is the most common form of PMG. Clinical signs include pseudobulbar paresis, mental retardation, and epilepsy. Familial forms of BPP have been described and a candidate locus was previously mapped to chromosome Xq28, distal do marker DXS8103. The objective of this study was to perform linkage analysis in one family segregating BPP. A total of 15 individuals, including 8 affected patients with BPP were evaluated. Family members were examined by a neurologist and subjected to magnetic resonance imaging scans. Individuals were genotyped for 18 microsatellite markers, flanking a 42.3 cM interval on ch Xq27-q28. Two-point and multipoint linkage analysis was performed using the LINKAGE package and haplotype reconstruction was performed by GENEHUNTER software. Our results showed a wide spectrum of clinical manifestations in affected individuals with BPP, ranging from normal to mild neurological abnormalities. Two-point linkage analysis yield a Zmax = 2.06 at theta = 0.00 for markers DXS1205 and DXS1227. Multipoint lod-scores indicate a candidate interval of 13 cM between markers DSXS1205 and DXS8043, on ch Xq27.2-Xq27.3. These results point to a new locus for BPP in a more centromeric location than previously reported.

Assessing the Impact of Issue Linkage in the Common Fisheries Policy

AbstractAlthough issue linkage is often an important variable in negotiations, it remains an underdeveloped research area in European integration studies. This article attempts to assess the impact of issue linkage on EU bargaining outcomes by applying the Tollison and Willett spatial model of issue linkage to a key bargaining situation in the common fisheries policy: the negotiations on the introduction of the common market organization and structural policy. This article attempts to demonstrate how deals can be completed through issue linkage packages and to identify the conditions that make issue linkage more likely.

The Role of the GABRA2 Polymorphism in Multiplex Alcohol Dependence Families With Minimal Comorbidity: Within-Family Association and Linkage Analyses

The genes encoding the gamma-aminobutyric acid(A) (GABA(A)) receptor have been the focus of several recent studies investigating the genetic etiology of alcohol dependence. Analyses of multiplex families found a particular gene, GABRA2, to be highly associated with alcohol dependence, using within-family association tests and other methods. Results were confirmed in three case-control studies. The objective of this study was to investigate the GABRA2 gene in another collection of multiplex families. Analyses were based on phenotypic and genotypic data available for 330 individuals from 65 bigenerational pedigrees with a total of 232 alcohol-dependent subjects. A proband pair of same-sex siblings meeting Diagnostic and Statistical Manual of Mental Disorders, Third Edition, criteria for alcohol dependence was required for entry of a family into the study. One member of the proband pair was identified while in treatment for alcohol dependence. Linkage and association of GABRA2 and alcohol dependence were evaluated using SIBPAL (a nonparametric linkage package) and both the Pedigree Disequilibrium Test and the Family-Based Association Test, respectively. We find no evidence of a relationship between GABRA2 and alcohol dependence. Linkage analyses exhibited no linkage using affected/affected, affected/unaffected, and unaffected/unaffected sib pairs (all p's < .13). There was no evidence of a within-family association (all p's > .39). Comorbidity may explain why our results differ from those in the literature. The presence of primary drug dependence and/or other psychiatric disorders is minimal in our pedigrees, although several of the other previously published multiplex family analyses exhibit a greater degree of comorbidity.

Study on the position of genes responsible for gallstone disease in Chinese population

To search the susceptibility genes of gallstone disease in Chinese population. A genome wide scan was performed in twelve families with gallstone disease using fluorescence-labeled microsatellite markers. Genehunter and Batchlink of Linkage package were used for non- parameter and parameter linkage analysis to search the linkage loci on chromosomes. Four loci of D3S1266, D4S406, D9S1682 and D11S902 showed suggestive evidence for linkage. nonparametric linkage analysis (NPL)-score of D4S406 and D9S1682 was 1.77 (P = 0.05) and 1.92 (P = 0.04) respectively. The corresponding logarithm of the odds ratio (LOD)-score of D3S1266, D9S1682 were 1.35 and 2.07, and showed a rise of LOD-score from 1.35 to 2.71, 2.07 to 2.40 respectively when families with later-found patients or with higher triglyceride level were analyzed alone. Transmitted disequilibrium test of D11S902 showed a P-value of 0.0027. Chromosome 3, 4, 9 and 11 may contain genes involved in gallstone disease in Chinese population, and chromosome 3, 9 may hide genes that are liked to gallstone disease in families with later-found patients or with higher triglyceride concentration.

Linkage analysis of alcohol dependence using MOD scores

Alcohol dependence is a typical example of a complex trait that is governed by several genes and for which the mode of inheritance is unknown. We analyzed the microsatellite markers and the Affymetrix single-nucleotide polymorphisms (SNPs) for a subset of the Collaborative Study on the Genetics of Alcoholism family sample, 93 pedigrees of Caucasian ancestry comprising 919 persons, 390 of whom are affected according to DSM III-R and Feighner criteria. In particular, we performed parametric single-marker linkage analysis using MLINK of the LINKAGE package (for the microsatellite data), as well as multipoint MOD-score analysis with GENEHUNTER-MODSCORE (for the microsatellite and SNP data). By use of two liability classes, different penetrances were assigned to males and females. In order to investigate parent-of-origin effects, we calculated MOD scores under trait models with and without imprinting. In addition, for the microsatellite data, the MOD-score analysis was performed with sex-averaged as well as sex-specific maps. The highest linkage peaks were obtained on chromosomes 1, 2, 7, 10, 12, 13, 15, and 21. There was evidence for paternal imprinting at the loci on chromosomes 2, 10, 12, 13, 15, and 21. A tendency to maternal imprinting was observed at two loci on chromosome 7. Our findings underscore the fact that an adequate modeling of the genotype-phenotype relation is crucial for the genetic mapping of a complex trait.

Individual-Specific Liability Groups in Genetic Linkage, with Applications to Kindreds with Li-Fraumeni Syndrome

In this report, we present a simple and powerful way to incorporate individual-specific liability classes into linkage analysis. The proposed method is applicable to both quantitative and qualitative traits. In linkage studies, we may have information about different covariates. Incorporation of these covariates along with the estimates of residual familial effects, age-at-onset effects, and susceptibility in the definition of liability classes can increase the power to detect genetic linkage. In this study, we show how one can form individual-specific liability classes and use these classes in standard linkage-analysis programs, such as the widely used LINKAGE package, to perform more powerful genetic linkage analysis. Our simulation study shows that this approach yields higher LOD scores and more-accurate estimates of the recombination fraction in the families showing linkage. The proposed method is also applied to kindreds collected, at the M. D. Anderson Cancer Center, through probands with childhood soft-tissue sarcoma. Confirmed germ-line mutations in the p53 tumor-suppressor gene have been identified in these families. Application of our method to these families yielded significantly higher LOD scores and more-accurate recombination fractions than did analysis that did not account for individual-specific covariate information.

Efforts to Initiate Construction of a Disease Resistance Package on a Designer Chromosome in Tobacco

Gene cloning and transformation can be used to circumvent linkage drag effects that can plague conventional interspecific gene transfers. These techniques can also be used to create desirable genetic linkages. Use of Nicotiana glutinosa L. N‐gene mediated TMV (tobacco mosaic virus) resistance in flue‐cured tobacco, N tabacum L., has been limited due to linkage drag effects. Transformation was used to introduce the cloned N‐gene into NC152, a chromosome addition line possessing a chromosome pair from N africana. This chromosome has been proposed to be used as a “designer chromosome” into which numerous transgenes could be inserted to form a desirable linkage package. The system could be used to shuttle a large number of transgenes from genotype to genotype. One hundred thirty‐six primary transformants possessing the N transgene were produced and hybridized with TMV‐susceptible ‘Petite Havana.’ These may serve as valuable TMV‐resistant breeding materials. For each independent transformant, BC1F1 families which segregated for TMV resistance and the addition chromosome were generated. Data from cosegregation, transmission, and molecular analyses were used to conclude that one transformant possessed an insertion of the N‐gene in the addition chromosome. By inserting N in the chromosome, we initiated construction of a disease resistance package by linking the TMV resistance gene with a potyvirus resistance gene(s) native to the chromosome. Occasional loss of the transgene, however, may be evidence of previously undetected interchromosomal recombination, and may have implications for use of this system in cultivar development.

Genome scans for Q1 and Q2 on general population replicates using Loki.

The Markov Chain Monte Carlo linkage package Loki was used to perform a genome scan under realistic conditions (using a 10-cM marker map without marker data on unsampled individuals, analyzing each chromosome separately, and without knowing the answers) for traits Q1 and Q2 on general population replicate 1. Using this approach we detected and correctly localized MG1 for Q1 and MG3 for Q2. We then repeated the analyses on replicate 1 and the "best replicate" (42) adding more information (using marker data on everyone, fitting a polygenic effect, and analyzing multiple chromosomes jointly) to see the effect on the detection of trait loci. We found that adding more data often improves the quality of the linkage signal, and reduces the false positive rate, but did not allow the detection of trait loci missed by the initial analysis. We also investigated the convergence of the sampler by repeating one multi-chromosome analysis six times with different random number seeds. We concluded that a strategy of performing a single chromosome scan using a moderate number of sampling iterations, followed by a multi-chromosome analysis of all chromosomes with linkage signals detected in the first scan using a longer sampling run, was an effective way of performing a genome scan on this data set.

Molecular characterisation of congenital glaucoma in a consanguineous Canadian community: a step towards preventing glaucoma related blindness

Glaucoma is a leading cause of irreversible blindness in Canada. Congenital glaucoma usually manifests during the first years of life and is characterised by severe visual loss and autosomal recessive...

Localization of a gene for familial juvenile hyperuricemic nephropathy causing underexcretion-type gout to 16p12 by genome-wide linkage analysis of a large family.

Familial juvenile hyperuricemic nephropathy (FJHN, MIM 162000) is an autosomal-dominant disease characterized by underexcretion-type hyperuricemia, gout, and chronic renal failure. No loci responsible for this disease or any underexcretion-type hyperuricemia/gout have ever been identified. The aim of the study was to localize a gene responsible for FJHN by linkage analysis. A single large family with at least 20 affected members was analyzed. DNA was obtained from 13 affected and 18 non-affected members after lymphoblastoid cell lines were established. Initially, polymorphic data were obtained for 343 microsatellite loci covering all chromosomes except the X chromosome. Parametric linkage analysis was performed using the obtained data with LINKAGE package software. Following a genome-wide search using a set of highly polymorphic microsatellite markers, initial evidence for linkage was obtained for a marker on chromosome 16p. We subsequently genotyped the same subjects for 12 additional markers spanning approximately 30 cM on the short arm of chromosome 16. We obtained a maximum 2-point logarithm of odds (LOD) score of 6.04 at theta = 0 with the marker D16S401; multipoint linkage analysis yielded a maximum LOD score of 6.14 with markers D16S401 and D16S3113, and established a minimum candidate interval of approximately 9 cM. A gene for FJHN was localized to a candidate interval of approximately 9 cM at 16p12. These findings will be useful for the presymptomatic diagnosis of FJHN in some families and for testing genetic heterogeneity of FJHN in general.