Genome Scanning for Segments Shared Identical by Descent among Distant Relatives in Isolated Populations

Abstract

In this paper, we address some of the statistical issues concerning false-positive rates that arise when the whole genome, or a portion thereof, is scanned in distantly related individuals, to search for a disease locus. We derive a method for correcting false-positive probabilities for the large number of comparisons that are performed when scanning a large portion of the genome. We consider both the idealized situation of a dense set of fully informative markers and the more realistic data-collection strategy of an initial scan at low resolution to identify promising areas, which then are typed with markers at high resolution. We also examine the accuracy of false-positive rates approximated using a conservative estimate of the separation distance between affected individuals in the current generation and the common ancestral couple. Calculation of false-positive rates when inbreeding is present in the pedigree also is considered.

A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands

“…Furthermore, a haplotype (271-2) of the two-marker segments D3S3594-D3S3589 at 32.36 cM was close to significantly more frequent among cases than controls, and the probability (P 0 and P 1 ) that six out of 22 haplotypes are shared IBD 0 in cases related 7.2 generations ago is as small as 2.7 Â 10 À8 and 1.7 Â 10 À7 , respectively, according to the formula of Houwen 39 and P 2 ¼ 3.7 Â 10 À5 according to Durham and Feingold. 40 The frequency of allele 206 of marker D15S198 on chromosome 15q also appeared to be significantly different among cases compared to controls. A single haplotype (206-7) of the twomarker segment D15S198-D15S643, spanning 51.21-52.33 cM, proved to have significantly higher frequency among cases compared to controls, and IBD 0 calculations showed that IBD 0 is less likely.…”

“…In order to determine whether a potential association between autism and related PDDs and single-or two-marker segments is due to IBD 0 , the probability that affected individuals share a haplotype that is IBD 0 from a known ancestor through a specific genealogical relationship was calculated using the formulas derived by Houwen et al 39 and Durham & Feingold. 40 In these formulas, the average pairwise relationship with a common ancestor of the 12 individuals with autism and related PDDs were used. P 0 is the probability of the observed number of cases having the most frequent haplotype IBD 0 from a known ancestor (i.e.…”

“…P 2 is the genome wide probability of IBD 0 according to the method by Durham & Feingold. 40 This was done for segments with a low CLUMP P-value (Pp0.01) for haplotypes with a higher frequency among cases compared to controls.…”

Sharing of a conserved haplotype suggests a susceptibility gene for multiple sclerosis at chromosome 17p11

“…The failure to detect other haplotypes could depend on insufficient density of the present marker map, or on the use of a limited number of affected individuals in the first screen in which only five patients were genotyped extensively. Durham and Freingold, 29 using a simulation analysis, proposed that the median size of a segment shared IBD by five chromosomes, with a separation distance of six meiosis, is only *5.5 cM. Therefore, an optimal analysis of the present material might require an increased number of nuclear families in an initial screen and a denser marker map.…”

“…The chance of a false positive finding in a genome-wide analysis such as the present must be taken into account, although the theoretical risk has been evaluated using simulation analysis. 15,29 In general, the shared haplotype method is considered to give a low rate of false positives. To minimise false positive findings in the initial screen, we set up the strict criteria outlined above.…”