Biology subjects

Simpson, M. A.

Publications and source records attributed to Simpson, M. A..

3 recordsLinked to original sources

bioRxiv2017

Exome sequencing and genotyping identify a rare variant in NLRP7 gene associated with ulcerative colitis.

Background and aimsAlthough genome-wide association studies (GWAS) in inflammatory bowel disease (IBD) have identified a large number of common disease susceptibility alleles for both Crohns disease (CD) and ulcerative colitis (UC), a substantial fraction of IBD heritability remains unexplained, suggesting that rare coding genetic variants may also have a role in pathogenesis. We used high-throughput sequencing in families with multiple cases of IBD, followed by genotyping of cases and controls, to investigate whether rare protein altering genetic variants are associated with susceptibility to IBD.\n\nMethodsWhole exome sequencing was carried out in 10 families in which 3 or more individuals were affected with IBD. A stepwise filtering approach was applied to exome variants to identify potential causal variants. Follow-up genotyping was performed in 6,025 IBD cases (2,948 CD; 3,077 UC) and 7,238 controls.\n\nResultsOur exome variant analysis revealed coding variants in the NLRP7 gene that were present in affected individuals in two distinct families. Genotyping of the two variants, p.S361L and p.R801H, in IBD cases and controls showed that the p.S361L variant was significantly associated with an increased risk of ulcerative colitis (odds ratio 4.79, p=0.0039) and IBD (odds ratio 3.17, p=0.037). A combined analysis of both variants showed suggestive association with an increased risk of IBD (odds ratio 2.77, p=0.018).\n\nConclusionsThe results suggest that NLRP7 signalling and inflammasome formation may be a significant component in the pathogenesis of IBD.

genetics↗

bioRxiv2017

A mutation in the LMOD1 actin-binding domain segregating with disease in a large British family with thoracic aortic aneurysms and dissections

We describe a mutation in LMOD1, which predisposes individuals to thoracic aortic aneurysms and dissections in a large multi-generation British family. Exome variant profiles for the proband and two distantly related affected relatives were generated and a rare protein-altering, heterozygous variant was identified, present in all the exome-sequenced affected individuals. The allele c.1784T>C, p.(V595A) in LMOD1 is located in a known actin-binding WH2 domain and is carried by all living affected individuals in the family. LMOD1 was further assessed in a consecutive series of 98 UK TAAD patients and one further mutation was found, yielding an incidence of [~]2% in our study group. Assessment of LMOD1 in international TAAD cohorts discovered nine other missense variants of which three were classed as likely pathogenic.\n\nValidation of LMOD1 was undertaken using a zebrafish animal model. Knock-down of both lmod1a and lmod1b paralogs using morpholino oligonucleotides showed a reproducible abnormal phenotype involving the aortic arches under off-target controls. Injection of the human LMOD1 c.1784T>C, p.(V595A) mutation demonstrated a likely dominant negative effect and illustrated a loss of function cause.\n\nMutations found in the WH2 actin-binding domain of LMOD1 may delay actin polymerization and therefore compromise actin length, dynamics and interaction with myosin in the smooth muscle contraction pathway.

genetics↗

bioRxiv2017

De Novo Mutations Implicate Novel Genes With Burden Of Rare Variants In Systemic Lupus Erythematosus

The omnigenic model of complex diseases stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing (WES), high-density imputation, and in vitro cellular assays, we identify three candidate core genes in the pathogenesis of Systemic Lupus Erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies (GWAS). In a follow-up cohort of 10,995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. We identify a burden of rare variants across PRKCD associated with SLE risk (P=0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P=0.0005 and P=0.0033). Both genes are functional candidates and significantly constrained against missense mutations in gene-level analyses, along with C1QTNF4. We further characterise the TNF-dependent functions of candidate gene C1QTNF4 on NF-{kappa}B activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.\n\nSignificance StatementRare variants, present in <1% in population, are expected to explain little of the heritability of complex diseases, such as Systemic Lupus Erythematosus (SLE), yet are likely to identify core genes crucial to disease mechanisms. Their rarity, however, limits the power to show their statistical association with disease. Through sequencing the exomes of SLE patients and their parents, we identified non-inherited de novo mutations in 14 genes and hypothesised that these are prime candidates for harbouring additional disease-associated rare variants. We demonstrate that two of these genes also carry a significant excess of rare variants in an independent, large cohort of SLE patients. Our findings will influence future study designs in the search for the missing heritability of complex diseases.

genetics↗