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Rare coding variants pinpoint genes that control human hematological traits.

Abstract The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45-0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos genetics
Publication Year Start




PMID- 28787443
OWN - NLM
STAT- Publisher
DA  - 20170808
LR  - 20170808
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Linking)
VI  - 13
IP  - 8
DP  - 2017 Aug 07
TI  - Rare coding variants pinpoint genes that control human hematological traits.
PG  - e1006925
LID - 10.1371/journal.pgen.1006925 [doi]
AB  - The identification of rare coding or splice site variants remains the most
      straightforward strategy to link genes with human phenotypes. Here, we analyzed
      the association between 137,086 rare (minor allele frequency (MAF) &lt;1%) coding or
      splice site variants and 15 hematological traits in up to 308,572 participants.
      We found 56 such rare coding or splice site variants at P&lt;5x10-8, including 31
      that are associated with a blood-cell phenotype for the first time. All but one
      of these 31 new independent variants map to loci previously implicated in
      hematopoiesis by genome-wide association studies (GWAS). This includes a rare
      splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33)
      associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of
      asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45-0.70])
      and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single
      new locus identified in our study is defined by a rare p.Arg172Gly missense
      variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased
      platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018)
      and platelet reactivity (P&lt;0.03). Finally, our results indicate that searching
      for rare coding or splice site variants in very large sample sizes can help
      prioritize causal genes at many GWAS loci associated with complex human diseases 
      and traits.
FAU - Mousas, Abdou
AU  - Mousas A
AUID- ORCID: http://orcid.org/0000-0001-7695-8029
AD  - Department of Medicine, Universite de Montreal, Montreal, Quebec, Canada.
AD  - Montreal Heart Institute, Montreal, Quebec, Canada.
FAU - Ntritsos, Georgios
AU  - Ntritsos G
AD  - Department of Hygiene and Epidemiology, University of Ioannina Medical School,
      Ioannina, Greece.
FAU - Chen, Ming-Huei
AU  - Chen MH
AD  - Population Sciences Branch, National Heart Lung and Blood Institute, The
      Framingham Heart Study, Framingham, MA, United States of America.
FAU - Song, Ci
AU  - Song C
AUID- ORCID: http://orcid.org/0000-0002-0947-9068
AD  - Population Sciences Branch, National Heart Lung and Blood Institute, The
      Framingham Heart Study, Framingham, MA, United States of America.
FAU - Huffman, Jennifer E
AU  - Huffman JE
AUID- ORCID: http://orcid.org/0000-0002-9672-2491
AD  - Population Sciences Branch, National Heart Lung and Blood Institute, The
      Framingham Heart Study, Framingham, MA, United States of America.
FAU - Tzoulaki, Ioanna
AU  - Tzoulaki I
AUID- ORCID: http://orcid.org/0000-0002-4275-9328
AD  - Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and 
      Health, School of Public Health, Imperial College London, London, United Kingdom.
FAU - Elliott, Paul
AU  - Elliott P
AUID- ORCID: http://orcid.org/0000-0002-7511-5684
AD  - Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and 
      Health, School of Public Health, Imperial College London, London, United Kingdom.
FAU - Psaty, Bruce M
AU  - Psaty BM
AD  - Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and
      Health Services, University of Washington, Seattle, WA, United States of America.
AD  - Kaiser Permanente Washington Health Research Institute, Seattle, WA, United
      States of America.
CN  - Blood-Cell Consortium
FAU - Auer, Paul L
AU  - Auer PL
AD  - Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI,
      United States of America.
FAU - Johnson, Andrew D
AU  - Johnson AD
AD  - Population Sciences Branch, National Heart Lung and Blood Institute, The
      Framingham Heart Study, Framingham, MA, United States of America.
FAU - Evangelou, Evangelos
AU  - Evangelou E
AD  - Department of Hygiene and Epidemiology, University of Ioannina Medical School,
      Ioannina, Greece.
AD  - Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and 
      Health, School of Public Health, Imperial College London, London, United Kingdom.
FAU - Lettre, Guillaume
AU  - Lettre G
AUID- ORCID: http://orcid.org/0000-0002-7740-3399
AD  - Department of Medicine, Universite de Montreal, Montreal, Quebec, Canada.
AD  - Montreal Heart Institute, Montreal, Quebec, Canada.
FAU - Reiner, Alexander P
AU  - Reiner AP
AD  - Department of Epidemiology, University of Washington, Seattle, WA, United States 
      of America.
AD  - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center,
      Seattle, WA, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20170807
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
EDAT- 2017/08/09 06:00
MHDA- 2017/08/09 06:00
CRDT- 2017/08/09 06:00
PHST- 2017/04/19 [received]
PHST- 2017/07/14 [accepted]
AID - 10.1371/journal.pgen.1006925 [doi]
AID - PGENETICS-D-17-00802 [pii]
PST - aheadofprint
SO  - PLoS Genet. 2017 Aug 7;13(8):e1006925. doi: 10.1371/journal.pgen.1006925.