Inferring rare disease risk variants based on exact probabilities of sharing by multiple affected relatives

Bureau, Alexandre; Younkin, Samuel G.; Parker, Margaret M.; Bailey-Wilson, Joan E.; Marazita, Mary L.; Murray, Jeffrey C.; Mangold, Elisabeth; Albacha-Hejazi, Hasan; Beaty, Terri H.; Ruczinski, Ingo

doi:10.1093/bioinformatics/btu198

Cited by 31 publications

(81 citation statements)

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“…Examining the empirical distribution of P-values from the exome-wide analysis revealed a good agreement with the uniform distribution, evidence of the general accuracy of these RV sharing probabilities (Bureau et al 2014, Figure S3). The number of novel SNVs predicted to be damaging (183 damaging SNVs in 348 candidate genes) was too small to undertake any analysis combining all SNVs in any one gene.…”

Section: Discussionmentioning

confidence: 71%

“…This excluded the novel SNV in CDH1 and all SNVs seen in single families. Highlights of these results were reported elsewhere (Bureau et al 2014) to illustrate our analytical approach based on RV sharing probabilities. We list in Table S2 the 80 SNVs yielding a P , 0.05.…”

Section: Discussionmentioning

confidence: 81%

“…Indeed, by restricting statistical testing to the 16 SNVs showing some potential to achieve a sufficiently low P-value, a novel SNV in gene CDH1 yielded significant evidence of cosegregation with cleft status in one family from India (see Figure 1). We also examined all rare and low frequency SNVs in exons and splice junctions with a MAF , 0.01 from all annotated genes (Bureau et al 2014).…”

Section: Discussionmentioning

confidence: 99%

“…For variants seen in only one family, this probability can be interpreted directly as a P-value from a Bernoulli trial. For variants seen in M families and shared by affected relatives in m of them, the appropriate P-value was obtained as the sum of the probability of events as or more extreme than the observed sharing in m out of M families (Bureau et al 2014).…”

Section: Assessing Evidence For Potentially Causal Snvsmentioning

confidence: 99%

“…The probabilities P(F j ) cancel from the numerator and the denominator of Equation 1. Mathematical expressions have been derived for the other terms, namely the probabilities that all sequenced subjects and at least one sequenced subject received the RV, given it was introduced into the pedigree by founder j (Bureau et al 2014). As an example, for three sequenced second cousins shown in Figure 1 (individuals 402, 404, and 405), the probability P(C 1 = C 2 = C 3 = 1|F j ) = ((1/2) 3 ) 3 = 1/512 when j is one of the two greatgrandparents (individuals 101 or 102 in Figure 1), i.e., a probability of (1/2) 3 of transmitting the variant through three meioses to each great-grandchild, raised to the power 3 because this event had to happen for all three of the second cousins.…”

Section: Assessing Evidence For Potentially Causal Snvsmentioning

confidence: 99%

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Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

et al. 2014

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A dozen genes/regions have been confirmed as genetic risk factors for oral clefts in human association and linkage studies, and animal models argue even more genes may be involved. Genomic sequencing studies should identify specific causal variants and may reveal additional genes as influencing risk to oral clefts, which have a complex and heterogeneous etiology. We conducted a whole exome sequencing (WES) study to search for potentially causal variants using affected relatives drawn from multiplex cleft families. Two or three affected second, third, and higher degree relatives from 55 multiplex families were sequenced. We examined rare single nucleotide variants (SNVs) shared by affected relatives in 348 recognized candidate genes. Exact probabilities that affected relatives would share these rare variants were calculated, given pedigree structures, and corrected for the number of variants tested. Five novel and potentially damaging SNVs shared by affected distant relatives were found and confirmed by Sanger sequencing. One damaging SNV in CDH1, shared by three affected second cousins from a single family, attained statistical significance (P = 0.02 after correcting for multiple tests). Family-based designs such as the one used in this WES study offer important advantages for identifying genes likely to be causing complex and heterogeneous disorders.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Assessing Evidence For Potentially Causal Snvsmentioning

confidence: 99%

Section: Assessing Evidence For Potentially Causal Snvsmentioning

confidence: 99%

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Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

et al. 2014

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Novel variants in ZNF34 and other brain‐expressed transcription factors are shared among early‐onset MDD relatives

Subaran

Odgerel

Swaminathan

et al. 2016

American J of Med Genetics Pt B

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There are no known genetic variants with large effects on susceptibility to major depressive disorder (MDD). Although one proposed study approach is to increase sensitivity by increasing sample sizes, another is to focus on families with multiple affected individuals to identify genes with rare or novel variants with strong effects. Choosing the family-based approach, we performed whole-exome analysis on affected individuals (n = 12) across five MDD families, each with at least five affected individuals, early onset, and prepubertal diagnoses. We identified 67 genes where novel deleterious variants were shared among affected relatives. Gene ontology analysis shows that of these 67 genes, 18 encode transcriptional regulators, eight of which are expressed in the human brain, including four KRAB-A box-containing Zn2+ finger repressors. One of these, ZNF34, has been reported as being associated with bipolar disorder and as differentially expressed in bipolar disorder patients compared to healthy controls. We found a novel variant—encoding a non-conservative P17R substitution in the conserved repressor domain of ZNF34 protein—segregating completely with MDD in all available individuals in the family in which it was discovered. Further analysis showed a common ZNF34 coding indel segregating with MDD in a separate family, possibly indicating the presence of an unobserved, linked, rare variant in that particular family. Our results indicate that genes encoding transcription factors expressed in the brain might be an important group of MDD candidate genes and that rare variants in ZNF34 might contribute to susceptibility to MDD and perhaps other affective disorders.

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Analysis of high‐risk pedigrees identifies 11 candidate variants for Alzheimer's disease

Teerlink

Miller

Vance

et al. 2021

Alzheimer's & Dementia

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Introduction: Analysis of sequence data in high-risk pedigrees is a powerful approach to detect rare predisposition variants. Methods: Rare, shared candidate predisposition variants were identified from exome sequencing 19 Alzheimer's disease (AD)-affected cousin pairs selected from high-risk pedigrees. Variants were further prioritized by risk association in various external datasets. Candidate variants emerging from these analyses were tested for co-segregation to additional affected relatives of the original sequenced pedigree members.Results: AD-affected high-risk cousin pairs contained 564 shared rare variants.Eleven variants spanning 10 genes were prioritized in external datasets: rs201665195 (ABCA7), and rs28933981 (TTR) were previously implicated in AD pathology; rs141402160 (NOTCH3) and rs140914494 (NOTCH3) were previously reported; rs200290640 (PIDD1) and rs199752248 (PIDD1) were present in more than one cousin pair; rs61729902 (SNAP91), rs140129800 (COX6A2, AC026471), and rs191804178 (MUC16) were not present in a longevity cohort; and rs148294193 (PELI3) and rs147599881 (FCHO1) approached significance from analysis of AD-related phenotypes. Three variants were validated via evidence of co-segregation to additional relatives (PELI3, ABCA7, and SNAP91).Discussion: These analyses support ABCA7 and TTR as AD risk genes, expand on previously reported NOTCH3 variant identification, and prioritize seven additional candidate variants.

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Inferring rare disease risk variants based on exact probabilities of sharing by multiple affected relatives

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 31 publications

References 13 publications

Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

Novel variants in ZNF34 and other brain‐expressed transcription factors are shared among early‐onset MDD relatives

Analysis of high‐risk pedigrees identifies 11 candidate variants for Alzheimer's disease

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