Shared Genomic Segment Analysis: The Power to Find Rare Disease Variants

Knight, Stacey; Abo, Ryan; Abel, Haley J.; Neklason, Deborah W.; Tuohy, Thérèse M.F.; Burt, Randall W.; Thomas, Alun; Camp, Nicola J.

doi:10.1111/j.1469-1809.2012.00728.x

Cited by 21 publications

(33 citation statements)

References 28 publications

(34 reference statements)

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“…Of note, the 9 affected subjects shared by cluster 1 and 3 fell in a multiplex pedigree (K1584) previously identified by epidemiological studies in Palau [27]. SSA [34,35] was used to determine if 4q28.3 is the only region of the genome thus shared among these 11 and 9 affected subjects. For these affected subjects, only the same 4q28 region was identified (fig.…”

Section: Resultsmentioning

confidence: 99%

“…A statistic of some utility for pedigree-based linkage analysis is the total number of meioses separating all affected subjects in the pedigree [see [34], [35]]. Counting meioses in a pedigree is straightforward.…”

Section: Methodsmentioning

confidence: 99%

“…This approach relies on inferred haplotypes; when phase is erroneous, it yields false negatives. To characterize segment sharing without declaring phase, we analyzed subsets of subjects using shared segment analysis (SSA) [34,35]. For a given set, such as a pedigree, SSA searches the genome for regions of identity by state sharing among all or a subset of the subjects based on their genotypes, not haplotypes.…”

Section: Methodsmentioning

confidence: 99%

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Analysis of Shared Haplotypes amongst Palauans Maps Loci for Psychotic Disorders to 4q28 and 5q23-q31

et al. 2016

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To localize genetic variation affecting risk for psychotic disorders in the population of Palau, we genotyped DNA samples from 203 Palauan individuals diagnosed with psychotic disorders, broadly defined, and 125 control subjects using a genome-wide single nucleotide polymorphism array. Palau has unique features advantageous for this study: due to its population history, Palauans are substantially interrelated; affected individuals often, but not always, cluster in families; and we have essentially complete ascertainment of affected individuals. To localize risk variants to genomic regions, we evaluated long-shared haplotypes, ≥10 Mb, identifying clusters of affected individuals who share such haplotypes. This extensive sharing, typically identical by descent, was significantly greater in cases than population controls, even after controlling for relatedness. Several regions of the genome exhibited substantial excess of shared haplotypes for affected individuals, including 3p21, 3p12, 4q28, and 5q23-q31. Two of these regions, 4q28 and 5q23-q31, showed significant linkage by traditional LOD score analysis and could harbor variants of more sizeable risk for psychosis or a multiplicity of risk variants. The pattern of haplotype sharing in 4q28 highlights PCDH10, encoding a cadherin-related neuronal receptor, as possibly involved in risk.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Analysis of Shared Haplotypes amongst Palauans Maps Loci for Psychotic Disorders to 4q28 and 5q23-q31

et al. 2016

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“…10 Results indicated that if families had at least 15 meioses between cases, 3-10 families were sufficient to gain excellent power (>80%) to see at least one true positive within any given family. For all scenarios considered, genome-wide association studies would have had negligible power.…”

Section: Sample This Project Is Possible Because Of a 20-year Collabmentioning

confidence: 99%

Genomewide significant regions in 43 Utah high-risk families implicate multiple genes involved in risk for completed suicide

Coon

Darlington

DiBlasi

et al. 2017

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Suicide is the 10th leading cause of death in the US. While environment has undeniable impact, evidence suggests that genetic factors play a major role in completed suicide. We have >4,500 DNA samples from completed suicides through a collaboration with the Utah Medical Examiner. We have linked the records from these cases to the Utah Population Database which includes multi-generation genealogies, demographic data, and medical information on over 8 million individuals. This linking has resulted in extended families (7-9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed DNA from 215 suicide cases in 43 of our largest high-risk families and identified 16 regions with genome-wide significance in 10 families. Of the 163 genes in these regions, 25% were associated with psychiatric risk. We also found 13 regions with genome-wide suggestive evidence where the region overlaps in >1 family (p-values from 4.63E-09 to <1E-16). Of the 101 genes in these overlapping regions, seven have been previously associated with suicide risk (RGS18, BRINP3, RHEB, CDK5, CTNNA3, STAT1, and HTR2A); only one gene with specific suicide risk would have been expected by chance. Our most significant region on chromosome 5q23.3 was shared by 21 cases across three families. This region contains several genes associated with both psychiatric conditions and inflammation: HINT1, RAPGEF6, ACSL6, IL3, SLC22A4, CSF2, and IRF1. Our study provides 249 genes in the significant regions in our study represent important new candidate genes for suicide. The genome-wide significant family-specific regions may reveal more rare risk variants, while risk variants in regions that overlap across families may be more common.. CC-BY-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/195644 doi: bioRxiv preprint first posted online Sep. 28, 2017; 3 Author SummarySuicide is the 10th leading cause of death in the US. While environment has undeniable impact, evidence suggests that genetic factors play a major role in completed suicide. We have used DNA from suicide cases related to each other in very large extended high-risk families (7-9 generations) to discover regions of the genome likely to contain genetic changes leading to increased suicide risk. Studying these distantly related cases minimizes effects of shared environment and allows us to detect genetic risks more easily through their familial repetition. The genomic regions discovered in this study of our 43 largest high-risk families contained seven genes with corroborating evidence of association with suicide from previous studies, in addition to many genes with known psychiatric assoc...

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“…Genomewide association is well-suited to high-density SNP arrays, however, the power for this approach lies with the existence of high LD between a SNP on the platform and the underlying risk variant; which is vastly reduced with rare risk variants leading to low power [4,5]. Identity-by-descent (IBD) mapping, such as shared genomic segment (SGS) analysis, in extended pedigrees have been developed precisely for use with high-density SNP platforms and have been suggested to be more powerful than association analysis and traditional linkage analysis for the identification of rare variants [3,6,7]. The probability of IBD is a challenge to calculate in large pedigrees.…”

Section: Introductionmentioning

confidence: 99%

Pairwise shared genomic segment analysis in three Utah high-risk breast cancer pedigrees

et al. 2012

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BackgroundWe applied a new weighted pairwise shared genomic segment (pSGS) analysis for susceptibility gene localization to high-density genomewide SNP data in three extended high-risk breast cancer pedigrees.ResultsUsing this method, four genomewide suggestive regions were identified on chromosomes 2, 4, 7 and 8, and a borderline suggestive region on chromosome 14. Seven additional regions with at least nominal evidence were observed. Of particular note among these total twelve regions were three regions that were identified in two pedigrees each; chromosomes 4, 7 and 14. Follow-up two-pedigree pSGS analyses further indicated excessive genomic sharing across the pedigrees in all three regions, suggesting that the underlying susceptibility alleles in those regions may be shared in common. In general, the pSGS regions identified were quite large (average 32.2 Mb), however, the range was wide (0.3 – 88.2 Mb). Several of the regions identified overlapped with loci and genes that have been previously implicated in breast cancer risk, including NBS1, BRCA1 and RAD51L1.ConclusionsOur analyses have provided several loci of interest to pursue in these high-risk pedigrees and illustrate the utility of the weighted pSGS method and extended pedigrees for gene mapping in complex diseases. A focused sequencing effort across these loci in the sharing individuals is the natural next step to further map the critical underlying susceptibility variants in these regions.

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Shared Genomic Segment Analysis: The Power to Find Rare Disease Variants

Cited by 21 publications

References 28 publications

Analysis of Shared Haplotypes amongst Palauans Maps Loci for Psychotic Disorders to 4q28 and 5q23-q31

Analysis of Shared Haplotypes amongst Palauans Maps Loci for Psychotic Disorders to 4q28 and 5q23-q31

Genomewide significant regions in 43 Utah high-risk families implicate multiple genes involved in risk for completed suicide

Pairwise shared genomic segment analysis in three Utah high-risk breast cancer pedigrees

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