Stepwise oligogenic segregation and linkage analysis illustrated with dopamine‐β‐hydroxylase activity

Wilson, Alexander F.; Elston, Robert C.; Sellers, Thomas A.; Bailey-Wilson, Joan E.; Gersting, J. M.; Deen, Dasha; Sorant, Alexa J.M.; Tran, Lieu; Amos, Christopher I.

doi:10.1002/ajmg.1320350321

Cited by 22 publications

(17 citation statements)

References 18 publications

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“…Abbreviations: tyr, tyrosine; TH, tyrosine hydroxylase; AADC, aromatic L-amino acid decarboxylase Building on the early work of Elston et al (1979), Goldin et al (1982) reported positive evidence for linkage between a locus influencing plasma DβH activity and the blood-group locus ABO. This observation was confirmed and extended by Elston et al (Asamoah et al 1987;Wilson et al 1988Wilson et al , 1990, who reported a maximum lod score >5.0 between ABO and plasma DβH activity. Simultaneously, Lamouroux et al (1987) cloned the cDNA encoding DβH protein, permitting molecular mapping by fluorescent in situ hybridization (Craig et al 1988), and molecular linkage studies (Gelernter et al 1991;Perry et al 1991).…”

supporting

confidence: 80%

“…In other words, determination of genotypes at −1021C→T can factor out up to 50% of the inter-individual variance in plasma DβH. The residual variance presumably reflects a combination of other loci influencing plasma DβH (Wilson et al 1988(Wilson et al , 1990Province 2000), and environmental or physiological influences on the measure. The plethora of inconclusive studies of plasma DβH, published largely in the 1970's and 1980's, thus bears re-examination in genotypecontrolled studies.…”

Section: Genotype-controlled Analysis Of Plasma Dβh In Alcohol Dependmentioning

confidence: 97%

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Human genetics of plasma dopamine ?-hydroxylase activity: applications to research in psychiatry and neurology

2004

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supporting

confidence: 80%

Section: Genotype-controlled Analysis Of Plasma Dβh In Alcohol Dependmentioning

confidence: 97%

Human genetics of plasma dopamine ?-hydroxylase activity: applications to research in psychiatry and neurology

2004

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“…It is still possible that an as yet unidentified DBH gene or a member of a related gene family in another chromosomal region is responsible for dystonia in these latter families. Recent work (Wilson et al 1990) suggests that there may be a second locus involved in determining levels of plasma DBH activity. Molecular genetic analysis has thus excluded a role for the known DBH gene on 9q34 in multiple forms of hereditary dystonia and revealed that there must be at least two autosomal loci that can produce a primary dystonic syndrome.…”

Section: Discussionmentioning

confidence: 98%

Dopamine beta-hydroxylase gene excluded in four subtypes of hereditary dystonia

et al. 1991

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The hereditary dystonias include a clinically heterogeneous group of movement disorders varying in symptoms, age of onset, and drug responsiveness. Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, has been implicated in dystonia because of increased serum levels of DBH in some patients, the influence of catecholaminergic drugs on the human phenotypes, and altered norepinephrine levels in several brain regions in dystonia patients and in genetically dystonic rodents. In addition, markers linked to the dystonia gene in two ethnic groups map close to the DBH locus on human chromosome 9q34. Here we evaluate the inheritance of restriction fragment length polymorphisms near the DBH gene in families with four subtypes of hereditary dystonia: Jewish and non-Jewish, early onset, generalized idiopathic torsion dystonia (ITD); dopa-responsive dystonia; and myoclonic dystonia. In all families, obligate recombination events were observed between the DBH and dystonia genes, thus excluding the DBH gene as the primary defect.

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“…Because normal probability densities are used to model the genotypic distributions in quantitative linkage analysis, and these densities asymptotically approach, but never reach, zero in both tails, every individual has a non-zero probability for having each genotype. This is problematic when trying to identify recombination events that help to localize candidate regions, but methods have been developed to classify individuals based on their most probable genotype [27] .…”

Section: Brief Overview and History Of Linkage Analysismentioning

confidence: 99%

“…Many types of trait models can be used with this algorithm. These are outside the scope of this overview, but comprehensive reviews are available in several articles and texts [27,[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] . Ott [65] implemented the Elston-Stewart algorithm to calculate the likelihood ratio test for linkage in human families of arbitrary size in LIPED, the first widely available computer program for this purpose.…”

Section: Brief Overview and History Of Linkage Analysismentioning

confidence: 99%

Linkage Analysis in the Next-Generation Sequencing Era

Bailey-Wilson¹,

Wilson²

2011

Hum Hered

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Linkage analysis was developed to detect excess co-segregation of the putative alleles underlying a phenotype with the alleles at a marker locus in family data. Many different variations of this analysis and corresponding study design have been developed to detect this co-segregation. Linkage studies have been shown to have high power to detect loci that have alleles (or variants) with a large effect size, i.e. alleles that make large contributions to the risk of a disease or to the variation of a quantitative trait. However, alleles with a large effect size tend to be rare in the population. In contrast, association studies are designed to have high power to detect common alleles which tend to have a small effect size for most diseases or traits. Although genome-wide association studies have been successful in detecting many new loci with common alleles of small effect for many complex traits, these common variants often do not explain a large proportion of disease risk or variation of the trait. In the past, linkage studies were successful in detecting regions of the genome that were likely to harbor rare variants with large effect for many simple Mendelian diseases and for many complex traits. However, identifying the actual sequence variant(s) responsible for these linkage signals was challenging because of difficulties in sequencing the large regions implicated by each linkage peak. Current ‘next-generation’ DNA sequencing techniques have made it economically feasible to sequence all exons or the whole genomes of a reasonably large number of individuals. Studies have shown that rare variants are quite common in the general population, and it is now possible to combine these new DNA sequencing methods with linkage studies to identify rare causal variants with a large effect size. A brief review of linkage methods is presented here with examples of their relevance and usefulness for the interpretation of whole-exome and whole-genome sequence data.

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Stepwise oligogenic segregation and linkage analysis illustrated with dopamine‐β‐hydroxylase activity

Cited by 22 publications

References 18 publications

Human genetics of plasma dopamine ?-hydroxylase activity: applications to research in psychiatry and neurology

Human genetics of plasma dopamine ?-hydroxylase activity: applications to research in psychiatry and neurology

Dopamine beta-hydroxylase gene excluded in four subtypes of hereditary dystonia

Linkage Analysis in the Next-Generation Sequencing Era

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