Genome-wide association analysis of age-at-onset traits using Cox mixed-effects models

He, Liang; Kulminski, Alexander M.

doi:10.1101/729285

Cited by 3 publications

(4 citation statements)

References 69 publications

(78 reference statements)

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“…Note that we compared each mutant separately with iso- w 1118 flies since we only wanted to capture their changes in infection susceptibility relative to control flies. For each batch of flies, across pathogen types, sexes and age groups, we analysed the survival data with a mixed-effects Cox model, using the R package ‘coxme’ [30]. We specified the model as: survival approximately fly lines (individual AMP mutant lines versus iso- w 1118 ) + (1|food vials), with fly lines as a fixed effect and replicate food vials as a random effect.…”

Section: Methodsmentioning

confidence: 99%

Ageing leads to reduced specificity of antimicrobial peptide responses in Drosophila melanogaster

et al. 2022

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Evolutionary theory predicts a late-life decline in the force of natural selection, possibly leading to late-life deregulations of the immune system. A potential outcome of such deregulations is the inability to produce specific immunity against target pathogens. We tested this possibility by infecting multiple Drosophila melanogaster lines (with bacterial pathogens) across age groups, where either individual or different combinations of Imd- and Toll-inducible antimicrobial peptides (AMPs) were deleted using CRISPR gene editing. We show a high degree of non-redundancy and pathogen-specificity of AMPs in young flies: in some cases, even a single AMP could confer complete resistance. However, ageing led to drastic reductions in such specificity to target pathogens, warranting the action of multiple AMPs across Imd and Toll pathways. Moreover, use of diverse AMPs either lacked survival benefits or even accompanied survival costs post-infection. These features were also sexually dimorphic: females required a larger repertoire of AMPs than males but extracted equivalent survival benefits. Finally, age-specific expansion of the AMP-repertoire was accompanied with ageing-induced downregulation of negative-regulators of the Imd pathway and damage to renal function post-infection, as features of poorly regulated immunity. Overall, we could highlight the potentially non-adaptive role of ageing in producing less-specific AMP responses, across sexes and pathogens.

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Section: Methodsmentioning

confidence: 99%

Ageing leads to reduced specificity of antimicrobial peptide responses in Drosophila melanogaster

et al. 2022

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“…We did not exclude from LOADFS and CHS those subjects overlapping in ADSP as their proportion was small (475 for LOADFS and 834 for CHS) (Table S6). The coxmeg R package (He and Kulminski, 2019) was used to analyze the LOADFS data set with a GRM estimated from a genotype array, and the coxph function in the survival R package (Therneau and Lumley, 2015) was used to analyze the CHS, GenADA and ROSMAP data sets.…”

Section: Replication Analyses Confirm Snps In Ern1 Tacr3 and The Mapmentioning

confidence: 99%

“…The association analyses of the age-of-onset of AD in the discovery phase of ADSP was conducted using a Cox mixed-effects model implemented in the coxmeg R package (He and Kulminski, 2019), which accounted for the family structure in the cohort using a genetic relatedness matrix (GRM). A dense GRM was first estimated from the original WES data based on the GCTA model (Yang et al, 2011) implemented in the SNPRelate R package (Zheng et al, 2012).…”

Section: Exome-wide Age-of-onset Association Analysismentioning

confidence: 99%

“…We expect that discovery of additional AD associated genetic variants will provide more insights into the understanding of the AD pathology. analyses were performed using Cox mixed effects models implemented in the coxmeg R package (He and Kulminski, 2019). We built a genetic relatedness matrix (GRM) using the ADSP WES data to correct for relatedness of the subjects.…”

Section: Introductionmentioning

confidence: 99%

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Exome-wide age-of-onset analysis reveals exonic variants inERN1, TACR3andSPPL2Cassociated with Alzheimer’s disease

Loika

Park

et al. 2020

Preprint

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Despite recent discovery in GWAS of genomic variants associated with Alzheimer's disease (AD), its underlying biological mechanisms are still elusive. Discovery of novel AD-associated genetic variants, particularly in coding regions and from APOE ε 4 non-carriers, may provide more insights into the understanding of the pathology of AD. In this study, we carried out exome-wide association analysis of age-of-onset of AD with ~20,000 subjects, and placed more emphasis on APOE ε 4 non-carriers. Using Cox mixed-effects models, we find that age-of-onset shows a stronger genetic signal than AD case-control status, capturing many known variants with stronger significance, and also revealing three new variants. We identified two novel rare variants, rs56201815, a synonymous variant in ERN1, from the analysis of APOE ε 4 noncarriers, and a missense variant rs144292455 in TACR3. In addition, we detected rs12373123, a common missense variant in SPPL2C in the MAPT region, associated with age-of-onset of AD in APOE ε 4 non-carriers. In an attempt to unravel their regulatory and biological functions, we found that the minor allele of rs56201815 was associated with lower average FDG uptake across five brain regions in ADNI. Our eQTL analyses based on 6198 gene expression samples from ROSMAP and GTEx revealed that the minor allele of rs56201815 was associated with elevated expression of ERN1, a key gene triggering unfolded protein response (UPR), in multiple brain regions, including posterior cingulate cortex and nucleus accumbens. Our cell type-specific eQTL analysis of based on ~80,000 single nuclei in prefrontal cortex revealed that the protective minor allele of rs12373123 significantly increased expression of GRN in microglia, and was associated with MAPT expression in astrocytes. These findings provide novel evidence supporting the hypothesis of the potential involvement of the UPR to ER stress in the pathological pathway of AD, and also provide more insights into underlying regulatory mechanisms behind the pleiotropic effects of rs12373123 in multiple degenerative diseases including AD and Parkinson's disease.In this study, we performed exome-wide association analysis of age-of-onset of AD, in which most genetic variants are rare or low frequency, using an Alzheimer's Disease Sequencing Project (ADSP) sample of 10,216 subjects in the discovery phase. Rare coding variants often show larger effect size and their biological consequences are more explicable, but its association analysis is complicated by insufficient statistical power. Although exome-wide association of AD has recently been explored using AD status (Bis et al., 2018;Cruchaga et al., 2014;Raghavan et al., 2018), our rationale is that more AD-related rare variants can be identified using analysis of age-of-onset of AD with a Cox model given emerging evidence from a previous study showing its advantage in terms of statistical power (He and Kulminski, 2019). We attempted to replicate significant findings in four other studies, with a meta-analysis sample size of a...

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NEBULA: a fast negative binomial mixed model for differential expression and co-expression analyses of large-scale multi-subject single-cell data

Kulminski

2020

Preprint

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The growing availability of large-scale single-cell data revolutionizes our understanding of biological mechanisms at a finer resolution. In differential expression and co-expression analyses of multi-subject single-cell data, it is important to take into account both subject-level and cell-level overdispersions through negative binomial mixed models (NBMMs). However, the application of NBMMs to large-scale single-cell data is computationally demanding. In this work, we propose an efficient NEgative Binomial mixed model Using a Large-sample Approximation (NEBULA)), which analytically solves the high-dimensional integral in the marginal likelihood instead of using the Laplace approximation. Our benchmarks show that NEBULA dramatically reduces the running time by orders of magnitude compared to existing tools. We showed that NEBULA controlled false positives in identifying marker genes, while a simple negative binomial model produced spurious associations. Leveraging NEBULA, we decomposed between-subject and within-subject overdispersions of an snRNA-seq data set in the frontal cortex comprising ∼80,000 cells from a cohort of 48 individuals for Alzheimer’s diseases (AD). We observed that subpopulations and known subject-level covariates contributed substantially to the overdispersions. We carried out cell-type-specific transcriptome-wide within-subject co-expression analysis of APOE. The results revealed that APOE was most co-expressed with multiple AD-related genes, including CLU and CST3 in astrocytes, TREM2 and C1q genes in microglia, and ITM2B, an inhibitor of the amyloid-beta peptide aggregation, in both cell types. We found that the co-expression patterns were different in APOE2+ and APOE4+ cells in microglia, which suggest an isoform-dependent regulatory role in the immune system through the complement system in microglia. NEBULA opens up a new avenue for the broad application of NBMMs in the analysis of large-scale multi-subject single-cell data.

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Genome-wide association analysis of age-at-onset traits using Cox mixed-effects models

Cited by 3 publications

References 69 publications

Ageing leads to reduced specificity of antimicrobial peptide responses in Drosophila melanogaster

Ageing leads to reduced specificity of antimicrobial peptide responses in Drosophila melanogaster

Exome-wide age-of-onset analysis reveals exonic variants inERN1, TACR3andSPPL2Cassociated with Alzheimer’s disease

NEBULA: a fast negative binomial mixed model for differential expression and co-expression analyses of large-scale multi-subject single-cell data

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