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Functional SNP allele discovery (fSNPd): an approach to find highly penetrant, environmental-triggered genotypes underlying complex human phenotypes.

Published version
Peer-reviewed

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Authors

Stouffer, Kaitlin 
Nahorski, Michael 
Moreno, Pablo 
Sarveswaran, Nivedita  ORCID logo  https://orcid.org/0000-0002-2341-2142

Abstract

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.

Description

Keywords

Environmental trigger, Genetic predisposition, Phenotype, SNPs, Alleles, Cohort Studies, Exome, Gene-Environment Interaction, Genetic Predisposition to Disease, Genotype, Humans, Phenotype, Polymorphism, Single Nucleotide, Stevens-Johnson Syndrome

Journal Title

BMC Genomics

Conference Name

Journal ISSN

1471-2164
1471-2164

Volume Title

18

Publisher

Springer Science and Business Media LLC
Sponsorship
Addenbrooke's Charitable Trust (ACT) (9158)
Biotechnology and Biological Sciences Research Council (BB/N504142/1)
Wellcome Trust (via University College London (UCL)) (532344)
Biotechnology and Biological Sciences Research Council (1801406)