Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7

Luo, Yang; Lange, Katrina M. de; Jostins, Luke; Moutsianas, Loukas; Randall, Joshua C.; Kennedy, Nicholas A; Lamb, Christopher A; McCarthy, Shane; Ahmad, Tariq; Edwards, Cathryn; Serra, Eva; Hart, Ailsa; Hawkey, C. J.; Mansfield, John C.; Mowat, Craig; Newman, William G.; Nichols, Sam; Pollard, Martin; Satsangi, Jack; Simmons, Alison; Tremelling, Mark; Uhlig, Holm H.; Wilson, David C.; Lee, James C.; Prescott, Natalie J.; Lees, Charlie W; Mathew, Christopher G.; Parkes, Miles; Barrett, Jeffrey C.; Anderson, Carl A.

doi:10.1038/ng.3761

Cited by 152 publications

(114 citation statements)

References 56 publications

(67 reference statements)

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“…We observed a broad enrichment of rare LOXL1 non-synonymous variants in the normal controls compared to the XFS patients (OR = 0.46, P = 4.2 x 10 -7 ; Table 1). As the vast majority of non-synonymous variants do not exert functional effects [31][32][33][34] , we performed a second test restricting the analysis to aggregate only rare, non-synonymous variants conservatively predicted to be deleterious by all five functional effect prediction algorithms (SIFT, Polyphen 2-HumDiv, LRT score, MutationTaster, and Condel) 33 . In so doing, we observed a substantially larger protective effect size conferred by rare variant burden (OR = 0.18, P = 4.23 x 10 -11 ; Table 2).…”

Section: Resultsmentioning

confidence: 99%

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Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

et al. 2017

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Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations, and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR = 25, P =2.9 × 10−14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

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Section: Resultsmentioning

confidence: 99%

“…, Montserrat García 34,35 , Héctor González-Iglesias 34,35 , Pedro P. Rodríguez-Calvo 34,35 , Luis Fernández-Vega 34,35 , …”

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Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

et al. 2017

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“…common variant associations of array-based GWAS, the modest sample sizes of most sequencing studies to date have limited the discovery of rare and low-frequency variant associations (Auer et al, 2016;Fuchsberger et al, 2016;Luo et al, 2017).…”

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confidence: 99%

Combining sequence data from multiple studies: Impact of analysis strategies on rare variant calling and association results

Chen

Boehnke

Fuchsberger

2019

Genetic Epidemiology

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Individual sequencing studies often have limited sample sizes and so limited power to detect trait associations with rare variants. A common strategy is to aggregate data from multiple studies. For studying rare variants, jointly calling all samples together is the gold standard strategy but can be difficult to implement due to privacy restrictions and computational burden. Here, we compare joint calling to the alternative of single‐study calling in terms of variant detection sensitivity and genotype accuracy as a function of sequencing coverage and assess their impact on downstream association analysis. To do so, we analyze deep‐coverage (~82×) exome and low‐coverage (~5×) genome sequence data on 2,250 individuals from the Genetics of Type 2 Diabetes study jointly and separately within five geographic cohorts. For rare single nucleotide variants (SNVs): (a) ≥97% of discovered SNVs are found by both calling strategies; (b) nonreference concordance with a set of highly accurate genotypes is ≥99% for both calling strategies; (c) meta‐analysis has similar power to joint analysis in deep‐coverage sequence data but can be less powerful in low‐coverage sequence data. Given similar data processing and quality control steps, we recommend single‐study calling as a viable alternative to joint calling for analyzing SNVs of all minor allele frequency in deep‐coverage data.

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“…Fourth, it has been proposed that rare variantswhich are not included on GWAS chips but which could have much larger effect sizesmight account for some of the missing heritability. However, several studies have now been performed to attempt to identify rare disease-associated variants, but without much success 88,89 mirroring the situation in other diseases. 90 Fifth, because most GWAS SNPs are proxies for the true causal variant, estimates of variance based on these are likely to underestimate the true attributable risk at each locus.…”

Section: Overlap With Other Immune-mediated Diseases -Shared Featuresmentioning

confidence: 99%

Genome‐wide association studies in Crohn's disease: Past, present and future

2018

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Over the course of the past decade, genome‐wide association studies (GWAS) have revolutionised our understanding of complex disease genetics. One of the diseases that has benefitted most from this technology has been Crohn's disease (CD), with the identification of autophagy, the IL‐17/IL‐23 axis and innate lymphoid cells as key players in CD pathogenesis. Our increasing understanding of the genetic architecture of CD has also highlighted how a failure to suppress aberrant immune responses may contribute to disease development – a realisation that is now being incorporated into the design of new treatments. However, despite these successes, a significant proportion of disease heritability remains unexplained. Similarly, most of the causal variants at associated loci have not yet been identified, and even fewer have been functionally characterised. Because of the inarguable rise in the incidence of CD in regions of the world that previously had low disease rates, GWAS studies will soon have to shift from a largely Caucasian focus to include populations from other ethnic backgrounds. Future studies should also move beyond conventional studies of disease susceptibility into phenotypically driven ‘within‐cases’ analyses in order to explore the role of genetics in other important aspects of disease biology. These studies are likely to include assessments of prognosis and/or response to treatments and may be critical if personalised medicine is ever to become a reality.

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Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7

Cited by 152 publications

References 56 publications

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Combining sequence data from multiple studies: Impact of analysis strategies on rare variant calling and association results

Genome‐wide association studies in Crohn's disease: Past, present and future

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