Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland

Hästbacka, Johanna; Chapelle, Albert de la; Kaitila, Ilkka; Sistonen, Pertti; Weaver, Alix; Lander, Eric S.

doi:10.1038/ng1192-204

Cited by 458 publications

(301 citation statements)

References 22 publications

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“…We assumed that a random population sample of 39 091 would be expected to yield 137 HREMbearing individuals, based on our observed frequency of 3 in 856 controls, and we assumed that such a sample would form a fraction of 7.8 Â 10 À5 of all Europeans, based on a current population size of 500 million. We performed DMLE þ using a burn-in of 20 000 iterations followed by runs of 100 000 iterations, with population growth rates in Europe of 5%, 20 with a lower limit of 2.5% 21 and an upper limit of 8.5%, 22 and with a 25-year inter-generation time, with lower and upper limits of 20 and 30 years respectively.…”

Section: Snp Genotyping and Haplotype Analysismentioning

confidence: 99%

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

et al. 2012

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A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS þ / ÀFTD from five European cohorts (total n ¼ 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n ¼ 434) and controls (n ¼ 856). Haplotypes were analysed using PLINK and aged using DMLE þ . In a London clinic cohort, the HREM was the most common mutation in familial ALS þ / ÀFTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS þ / ÀFTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, Po10 À8 ). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.

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Section: Snp Genotyping and Haplotype Analysismentioning

confidence: 99%

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

et al. 2012

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“…The consequent proliferation of linkage studies required computationally efficient methods for genome-wide statistical analysis and fostered the growth of the field of statistical genetics. The difficulty of isolating the first mapped genes [18][19][20] spurred the development of physical maps and the adaptation of linkage disequilibrium (LD) analysis (previously a tool for basic population genetics) for finescale mapping 20,21 .…”

Section: Appropriate Technology and Statistics For Each Approachmentioning

confidence: 99%

The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology

2004

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Efforts to identify gene variants associated with susceptibility to common diseases use three approaches: pedigree and affected sib-pair linkage studies and association studies of population samples. The different aims of these study designs reflect their derivation from biological versus epidemiological traditions. Similar principles regarding determination of the evidence levels required to consider the results statistically significant apply to both linkage and association studies, however. Such determination requires explicit attention to the prior probability of particular findings, as well as appropriate correction for multiple comparisons. For most common diseases, increasing the sample size in a study is a crucial step in achieving statistically significant genetic mapping results. Recent studies suggest that the technology and statistical methodology will soon be available to make wellpowered studies feasible using any of these approaches.

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“…It is the method most commonly applied, although it is clear that other methods of disequilibLinkage or pedigree analysis remains the fundamen-rium mapping may make more efficient use of the data. tal paradigm by which genetic epidemiologists map loci For instance, Hill and Weir (1994) advance a maximum contributing to inherited disorders (Ott, 1991). In fact, likelihood method for disequilibrium between two loci, numerous genes having a major effect on human dis-a disease locus and marker locus, assuming that the eases have been mapped to within 1 cM using such population itself is in a steady state of constant populaanalyses.…”

Section: Introductionmentioning

confidence: 99%

“…We then show, via simple deterministic examples, analytic ing French Canadian, Italian, and Louisiana Acadian populations Hanauer et al, 1990; methods, and stochastic simulations, that the choice of linkage disequilibrium measure can have a substantial Richter et al, 1990;Pandolfo et al, 1990;Sirugo et al, 1992), myotonic dystrophy using Caucasian popula-impact on the accuracy and interpretability of the simple disequilibrium mapping method. In what follows tions (Harley et al, 1991;Tsilfidis et al, 1991), Lubag's disease using a Philippine population (Graeber et al, we restrict our discussion to marker loci having two alleles and a disease locus having two alleles, a ''dis-1992; Wilhelmsen et al, 1992), diastrophic dysplasia (Hä stbacka et al, 1992(Hä stbacka et al, , 1994, and infantile neuronal ease'' and a ''normal'' allele. Thus the haplotypes for the disease locus and any single marker locus can be ceroid lipofuscinosis (Hellsten et al, 1993) using a Finnish population, Huntington disease using Cauca-arrayed in a 2 1 2 table.…”

Section: Introductionmentioning

confidence: 99%

A Comparison of Linkage Disequilibrium Measures for Fine-Scale Mapping

1995

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studies is difficult because recombinations are rarely Linkage mapping generally localizes disease genes observed even within the large pedigrees that would to 1-to 2-cM regions of chromosomes. In theory, fur-be required for finer mapping of these loci (Boehnke, ther refinement of location can be achieved by popula-1994). tion-based studies of linkage disequilibrium betweenConsequently, it will often be the case that linkage disease locus alleles and alleles at adjacent markers. mapping of disease loci leaves about 1 Mb of DNA to One approach to localization, dubbed simple disequi-be searched by the molecular geneticist, which can be librium mapping, is to determine the relative location a daunting amount unless there are natural candidate of the disease locus by plotting disequilibrium values genes in the region (e.g., Shiang et al., 1994). Any against marker locations. We investigate the simple method that narrows the amount of DNA to be mapping properties of five disequilibrium measures, searched would be important. One such method uses the correlation coefficient D, Lewontin's D , the robust linkage disequilibrium to refine the location of the dis- occurs. When evolutionary forces can be ignored, inmapping because it is directly related to the recombicluding marker and disease locus mutation, any decay nation fraction between the disease and the marker loci, and it is invariant when disease haplotypes are in disequilibrium is due solely to recombination. Under sampled at a rate higher than their population fre-this ideal scenario, and provided that the time since quencies, as in a case-control study. D yields results the disease mutation is not too long, the pattern or comparable to those of d in many realistic settings. Of curve of disequilibrium between disease and marker the remaining three measures, Q, D, and d, Q yields loci will exhibit a single maximum that occurs at the the best results. From simulations of short-term evolu-disease locus. Consequently, the amount of linkage distion, all measures show some sensitivity to marker al-equilibrium between a disease allele and closely linked lele frequencies; however, as predicted by analytic re-genetic markers may yield valuable information results, Q, D, and d exhibit the greatest sensitivity to garding the location of the disease gene. variation in marker allele frequencies across loci.

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Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland

Cited by 458 publications

References 22 publications

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology

A Comparison of Linkage Disequilibrium Measures for Fine-Scale Mapping

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