Alzheimer's disease: rare variants with large effect sizes

Del‐Aguila, Jorge L.; Koboldt, Daniel C.; Black, Kathleen; Chasse, Rachel; Norton, Joanne; Wilson, Richard K.; Cruchaga, Carlos

doi:10.1016/j.gde.2015.07.008

Cited by 36 publications

(19 citation statements)

References 67 publications

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“…This is supported by previous studies in which multiple independent variants have been reported as causative 14 or increase AD risk in APP, PSEN1, PSEN2, APOE, TREM2, PLD3 and ABCA7. [15][16][17][18] In this study, we have observed similar effect of rare variants in SORL1 as in previous studies, both at single-variant level (rs117260922:G4A), and at a gene-based level in the sEOAD cohort, adding support to the role of rare missense variants in SORL1 as risk factors for AD. Although our sEOAD sample size (217 cases and 169 controls) was smaller than that of Nicolas et al 10 (484 cases and 498 controls), we still had enough statistical power (83.4%) to replicate the original finding (gene-based OR = 5.03).…”

Section: Discussionsupporting

confidence: 88%

SORL1 variants across Alzheimer’s disease European American cohorts

et al. 2016

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The accumulation of the toxic Aβ peptide in Alzheimer's disease (AD) largely relies upon an efficient recycling of amyloid precursor protein (APP). Recent genetic association studies have described rare variants in SORL1 with putative pathogenic consequences in the recycling of APP. In this work, we examine the presence of rare coding variants in SORL1 in three different European American cohorts: early-onset, late-onset AD (LOAD) and familial LOAD.

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Section: Discussionsupporting

confidence: 88%

SORL1 variants across Alzheimer’s disease European American cohorts

et al. 2016

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“…17 Although GWASs have successfully identified disease-associated loci, each locus accounts for only a small fraction of AD susceptibility, and a large proportion of AD heritability still remains unexplained. 18 There is great interest in investigating the role of rare variants in the etiology of AD. Application of the RV-GDT identified suggestive associations between AD and rare variants in AXIN1 (MIM: 603816; GenBank: NM_003502.3) and TNK1 (MIM: 608076; GenBank: NM_001251902.1).…”

Section: Introductionmentioning

confidence: 99%

The Rare-Variant Generalized Disequilibrium Test for Association Analysis of Nuclear and Extended Pedigrees with Application to Alzheimer Disease WGS Data

Zhang

Renton

et al. 2017

The American Journal of Human Genetics

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Whole-genome and exome sequence data can be cost-effectively generated for the detection of rare-variant (RV) associations in families. Causal variants that aggregate in families usually have larger effect sizes than those found in sporadic cases, so family-based designs can be a more powerful approach than population-based designs. Moreover, some family-based designs are robust to confounding due to population admixture or substructure. We developed a RV extension of the generalized disequilibrium test (GDT) to analyze sequence data obtained from nuclear and extended families. The GDT utilizes genotype differences of all discordant relative pairs to assess associations within a family, and the RV extension combines the single-variant GDT statistic over a genomic region of interest. The RV-GDT has increased power by efficiently incorporating information beyond first-degree relatives and allows for the inclusion of covariates. Using simulated genetic data, we demonstrated that the RV-GDT method has well-controlled type I error rates, even when applied to admixed populations and populations with substructure. It is more powerful than existing family-based RV association methods, particularly for the analysis of extended pedigrees and pedigrees with missing data. We analyzed whole-genome sequence data from families affected by Alzheimer disease to illustrate the application of the RV-GDT. Given the capability of the RV-GDT to adequately control for population admixture or substructure and analyze pedigrees with missing genotype data and its superior power over other family-based methods, it is an effective tool for elucidating the involvement of RVs in the etiology of complex traits.

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“…For serum urate-associated loci and gout, it has also been shown that rare variants contribute to disease pathogenesis 24 25. However, statistical confirmation of rare variants requires high-quality in-depth sequencing and large sample sizes, which is not the case for most GWAS performed to date in gout patients 26–28. With recent advancements in sequencing technologies, the study of rare-frequency and low-frequency variants has remarkably improved.…”

Section: Introductionmentioning

confidence: 99%

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout

Klück

Deuren

Cavalli³

et al. 2020

Ann Rheum Dis

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ObjectiveGout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout.MethodsVariant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout.ResultsWe identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher’s exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10−5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry.ConclusionHere, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.

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Alzheimer's disease: rare variants with large effect sizes

Cited by 36 publications

References 67 publications

SORL1 variants across Alzheimer’s disease European American cohorts

SORL1 variants across Alzheimer’s disease European American cohorts

The Rare-Variant Generalized Disequilibrium Test for Association Analysis of Nuclear and Extended Pedigrees with Application to Alzheimer Disease WGS Data

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout

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