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LoFtool : a gene intolerance score based on loss-of-function variants in 60 706 individuals

Fadista, João LU ; Oskolkov, Nikolay LU ; Hansson, Ola LU and Groop, Leif LU (2017) In Bioinformatics1998-01-01+01:00 33(4). p.471-474
Abstract

MOTIVATION: Depletion of loss-of-function (LoF) mutations may provide a rank of genic functional intolerance and consequently susceptibility to disease.

RESULTS: Here we have studied LoF mutations in 60 706 unrelated individuals and show that the most intolerant quartile of ranked genes is enriched in rare and early onset diseases and explains 87% of de novo haploinsufficient OMIM mutations, 17% more than any other gene scoring tool. We detected particular enrichment in expression of the depleted LoF genes in brain (odds ratio = 1.5; P-value = 4.2e-07). By searching for de novo haploinsufficient mutations putatively associated with neurodevelopmental disorders in four recent studies, we were able to explain 81% of them. Taken... (More)

MOTIVATION: Depletion of loss-of-function (LoF) mutations may provide a rank of genic functional intolerance and consequently susceptibility to disease.

RESULTS: Here we have studied LoF mutations in 60 706 unrelated individuals and show that the most intolerant quartile of ranked genes is enriched in rare and early onset diseases and explains 87% of de novo haploinsufficient OMIM mutations, 17% more than any other gene scoring tool. We detected particular enrichment in expression of the depleted LoF genes in brain (odds ratio = 1.5; P-value = 4.2e-07). By searching for de novo haploinsufficient mutations putatively associated with neurodevelopmental disorders in four recent studies, we were able to explain 81% of them. Taken together, this study provides a novel gene intolerance ranking system, called LoFtool, which may help in ranking genes of interest based on their LoF intolerance and tissue expression.

AVAILABILITY AND IMPLEMENTATION: The LoFtool gene scores are available in the Supplementary data CONTACT: joaofadista@gmail.comSupplementary information: Supplementary data are available at Bioinformatics online.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Bioinformatics1998-01-01+01:00
volume
33
issue
4
pages
471 - 474
publisher
Oxford University Press
external identifiers
  • wos:000397264100001
  • scopus:85020046273
ISSN
1367-4803
DOI
10.1093/bioinformatics/btv602
language
English
LU publication?
yes
id
7d3207be-0efd-4339-bd31-33c871c79a67
date added to LUP
2016-11-14 17:06:27
date last changed
2018-01-07 11:35:05
@article{7d3207be-0efd-4339-bd31-33c871c79a67,
  abstract     = {<p>MOTIVATION: Depletion of loss-of-function (LoF) mutations may provide a rank of genic functional intolerance and consequently susceptibility to disease.</p><p>RESULTS: Here we have studied LoF mutations in 60 706 unrelated individuals and show that the most intolerant quartile of ranked genes is enriched in rare and early onset diseases and explains 87% of de novo haploinsufficient OMIM mutations, 17% more than any other gene scoring tool. We detected particular enrichment in expression of the depleted LoF genes in brain (odds ratio = 1.5; P-value = 4.2e-07). By searching for de novo haploinsufficient mutations putatively associated with neurodevelopmental disorders in four recent studies, we were able to explain 81% of them. Taken together, this study provides a novel gene intolerance ranking system, called LoFtool, which may help in ranking genes of interest based on their LoF intolerance and tissue expression.</p><p>AVAILABILITY AND IMPLEMENTATION: The LoFtool gene scores are available in the Supplementary data CONTACT: joaofadista@gmail.comSupplementary information: Supplementary data are available at Bioinformatics online.</p>},
  author       = {Fadista, João and Oskolkov, Nikolay and Hansson, Ola and Groop, Leif},
  issn         = {1367-4803},
  language     = {eng},
  number       = {4},
  pages        = {471--474},
  publisher    = {Oxford University Press},
  series       = {Bioinformatics1998-01-01+01:00},
  title        = {LoFtool : a gene intolerance score based on loss-of-function variants in 60 706 individuals},
  url          = {http://dx.doi.org/10.1093/bioinformatics/btv602},
  volume       = {33},
  year         = {2017},
}