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Functional SNP allele discovery (fSNPd): an approach to find highly penetrant, environmental-triggered genotypes underlying complex human phenotypes.
Stouffer, Kaitlin; Nahorski, Michael; Moreno, Pablo; Sarveswaran, Nivedita; Menon, David; Lee, Michael; Geoffrey Woods, C.
Afiliação
  • Stouffer K; Cambridge Institute for Medical Research, Wellcome Trust and MRC Building, Addenbrooke's Hospital campus, Cambridge, UK.
  • Nahorski M; Cambridge Institute for Medical Research, Wellcome Trust and MRC Building, Addenbrooke's Hospital campus, Cambridge, UK.
  • Moreno P; Cambridge Institute for Medical Research, Wellcome Trust and MRC Building, Addenbrooke's Hospital campus, Cambridge, UK.
  • Sarveswaran N; Cambridge Institute for Medical Research, Wellcome Trust and MRC Building, Addenbrooke's Hospital campus, Cambridge, UK.
  • Menon D; Department of Academic Anesthesiology, Addenbrooke's Hospital Campus, Cambridge, UK.
  • Lee M; Department of Academic Anesthesiology, Addenbrooke's Hospital Campus, Cambridge, UK.
  • Geoffrey Woods C; Cambridge Institute for Medical Research, Wellcome Trust and MRC Building, Addenbrooke's Hospital campus, Cambridge, UK. cw347@cam.ac.uk.
BMC Genomics ; 18(1): 944, 2017 Dec 04.
Article em En | MEDLINE | ID: mdl-29202707
BACKGROUND: Significant human diseases/phenotypes exist which require both an environmental trigger event and a genetic predisposition before the disease/phenotype emerges, e.g. Carbamazepine with the rare SNP allele of rs3909184 causing Stevens Johnson syndrome, and aminoglycosides with rs267606617 causing sensory neural deafness. The underlying genotypes are fully penetrant only when the correct environmental trigger(s) occur, otherwise they are silent and harmless. Such diseases/phenotypes will not appear to have a Mendelian inheritance pattern, unless the environmental trigger is very common (>50% per lifetime). The known causative genotypes are likely to be protein-altering SNPs with dominant/semi-dominant effect. We questioned whether other diseases and phenotypes could have a similar aetiology. METHODS: We wrote the fSNPd program to analyse multiple exomes from a test cohort simultaneously with the purpose of identifying SNP alleles at a significantly different frequency to that of the general population. fSNPd was tested on trial cohorts, iteratively improved, and modelled for performance against an idealised association study under mutliple parameters. We also assessed the seqeuncing depath of all human exons to determine which were sufficiently well sequenced in an exome to be sued by fSNPd - by assessing forty exomes base by base. RESULTS: We describe a simple methodology for the detection of SNPs capable of causing a phenotype triggered by an environmental event. This uses cohorts of relatively small size (30-100 individuals) with the phenotype being investigated, their exomes, and thence seeks SNP allele frequencies significantly different from expected to identify potentially clinically important, protein altering SNP alleles. The strengths and weaknesses of this approach for discovering significant genetic causes of human disease are comparable to Mendelian disease mutation detection and Association Studies. CONCLUSIONS: The fSNPd methodology is another approach, and has potentially significant advantage over Association studies in needing far fewer individuals, to detect genes involved in the pathogenesis of a diseases/phenotypes. Furthermore, the SNP alleles identified alter amino acids, potentially making it easier to devise functional assays of protein function to determine pathogenicity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome de Stevens-Johnson / Predisposição Genética para Doença / Polimorfismo de Nucleotídeo Único / Interação Gene-Ambiente Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome de Stevens-Johnson / Predisposição Genética para Doença / Polimorfismo de Nucleotídeo Único / Interação Gene-Ambiente Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article