PMID- 25635822
OWN - NLM
STAT- MEDLINE
DCOM- 20151006
LR  - 20201217
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 1
DP  - 2015
TI  - Exome sequencing of 75 individuals from multiply affected coeliac families and 
      large scale resequencing follow up.
PG  - e0116845
LID - 10.1371/journal.pone.0116845 [doi]
LID - e0116845
AB  - Coeliac disease (CeD) is a highly heritable common autoimmune disease involving 
      chronic small intestinal inflammation in response to dietary wheat. The human 
      leukocyte antigen (HLA) region, and 40 newer regions identified by genome wide 
      association studies (GWAS) and dense fine mapping, account for  approximately 40% of the 
      disease heritability. We hypothesized that in pedigrees with multiple individuals 
      with CeD rare [minor allele frequency (MAF) <0.5%] mutations of larger effect 
      size (odds ratios of  approximately 2-5) might exist. We sequenced the exomes of 75 coeliac 
      individuals of European ancestry from 55 multiply affected families. We selected 
      interesting variants and genes for further follow up using a combination of: an 
      assessment of shared variants between related subjects, a model-free linkage 
      test, and gene burden tests for multiple, potentially causal, variants. We next 
      performed highly multiplexed amplicon resequencing of all RefSeq exons from 24 
      candidate genes selected on the basis of the exome sequencing data in 2,248 
      unrelated coeliac cases and 2,230 controls. 1,335 variants with a 99.9% 
      genotyping call rate were observed in 4,478 samples, of which 939 were present in 
      coding regions of 24 genes (Ti/Tv 2.99). 91.7% of coding variants were rare (MAF 
      <0.5%) and 60% were novel. Gene burden tests performed on rare functional 
      variants identified no significant associations (p<1x10(-3)) in the resequenced 
      candidate genes. Our strategy of sequencing multiply affected families with deep 
      follow up of candidate genes has not identified any new CeD risk mutations.
FAU - Mistry, Vanisha
AU  - Mistry V
AD  - Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 
      Newark Street, London E1 2AT, United Kingdom.
FAU - Bockett, Nicholas A
AU  - Bockett NA
AD  - Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 
      Newark Street, London E1 2AT, United Kingdom.
FAU - Levine, Adam P
AU  - Levine AP
AD  - Division of Medicine, University College London, London, WC1E 6JF, United 
      Kingdom.
FAU - Mirza, Muddassar M
AU  - Mirza MM
AD  - UCL Advanced Diagnostics, Molecular Profiling Laboratory, Sarah Cannon-UCL 
      Laboratories, Ground Floor, Shropshire House, 1 Capper Street, London, WC1E 6JA, 
      United Kingdom.
FAU - Hunt, Karen A
AU  - Hunt KA
AD  - Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 
      Newark Street, London E1 2AT, United Kingdom.
FAU - Ciclitira, Paul J
AU  - Ciclitira PJ
AD  - King's College London, Division of Diabetes and Nutritional Sciences, 
      Gastroenterology, The Rayne Institute, St Thomas' Hospital, Westminster Bridge 
      Road, London SE1 7EH, United Kingdom.
FAU - Hummerich, Holger
AU  - Hummerich H
AD  - Medical Research Council Prion Unit, Department of Neurodegenerative Disease, 
      University College London Institute of Neurology, London WC1N 3BG, United 
      Kingdom.
FAU - Neuhausen, Susan L
AU  - Neuhausen SL
AD  - Department of Population Sciences, Beckman Research Institute of City of Hope, 
      Duarte, California 91010, United States of America.
FAU - Simpson, Michael A
AU  - Simpson MA
AD  - Division of Genetics and Molecular Medicine, Kings College London School of 
      Medicine, 8th Floor Tower Wing, Guy's Hospital, London SE1 9RY, United Kingdom.
FAU - Plagnol, Vincent
AU  - Plagnol V
AD  - University College London Genetics Institute, Gower Street, London WC1E 6BT, 
      United Kingdom.
FAU - van Heel, David A
AU  - van Heel DA
AD  - Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 
      Newark Street, London E1 2AT, United Kingdom.
LA  - eng
GR  - G1001158/Medical Research Council/United Kingdom
GR  - R01 DK081645/DK/NIDDK NIH HHS/United States
GR  - G0000934/Medical Research Council/United Kingdom
GR  - Wellcome Trust/United Kingdom
GR  - 068545/Z/02/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150130
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
SB  - IM
MH  - Case-Control Studies
MH  - Celiac Disease/*genetics
MH  - *Exome
MH  - Female
MH  - Follow-Up Studies
MH  - Gene Frequency
MH  - Genetic Linkage
MH  - Genetic Predisposition to Disease
MH  - Humans
MH  - Male
MH  - Pedigree
MH  - Polymorphism, Single Nucleotide
MH  - Sequence Analysis, DNA
PMC - PMC4312029
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/01/31 06:00
MHDA- 2015/10/07 06:00
PMCR- 2015/01/30
CRDT- 2015/01/31 06:00
PHST- 2014/08/01 00:00 [received]
PHST- 2014/11/24 00:00 [accepted]
PHST- 2015/01/31 06:00 [entrez]
PHST- 2015/01/31 06:00 [pubmed]
PHST- 2015/10/07 06:00 [medline]
PHST- 2015/01/30 00:00 [pmc-release]
AID - PONE-D-14-32937 [pii]
AID - 10.1371/journal.pone.0116845 [doi]
PST - epublish
SO  - PLoS One. 2015 Jan 30;10(1):e0116845. doi: 10.1371/journal.pone.0116845. 
      eCollection 2015.