Bayesian meta‐analysis across genome‐wide association studies of diverse phenotypes

Trochet, Holly; Pirinen, Matti; Jostins, Luke; McVean, Gil; Cca., Spencer

doi:10.1002/gepi.22202

Cited by 31 publications

(28 citation statements)

References 48 publications

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“…Under model NULL the effect is not present in either of the migraine subtypes (i.e., the effect is zero); under model MO or MA the effect is present only in MO or only in MA but not in both; and under model BOTH, a non-zero effect is shared by both MO and MA. We used a Bayesian approach for model comparison that combines a bivariate Gaussian prior distribution on the two effect sizes with a bivariate Gaussian approximation to the likelihood using GWAS summary statistics (Trochet et al, 2019). Across all models, the prior standard deviation for the effect is 0.2 on the log-odds scale for non-zero effects and 0 for a zero effect.…”

Section: Methodsmentioning

confidence: 99%

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Hautakangas¹,

Bs²,

Se³

et al. 2021

Preprint

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Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. This genome-wide association study (GWAS) of 102,084 migraine cases and 771,257 controls identified 123 loci of which 86 are novel. The loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. A stratification of the risk loci using 29,679 cases with subtype information, of which approximately half have never been used in a GWAS before, indicated three risk variants that appear specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that appear specific for migraine without aura (near SPINK2 and near FECH), and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

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Section: Methodsmentioning

confidence: 99%

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Hautakangas¹,

Bs²,

Se³

et al. 2021

Preprint

Self Cite

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“…To reflect the sparsity of genetic effects, we randomly selected p 0 = 100 of the p = 7, 563 variants to be causal. Motivated by Trochet et al [41], we drew the causal effect sizes from a bivariate normal distribution to model the similarity of genetic effects between ancestries. Denoting to be the indices of the causal SNPs, and we have the equation where ρ is the correlation between the ancestry-specific genetic effects.…”

Section: Methodsmentioning

confidence: 99%

Optimal strategies for learning multi-ancestry polygenic scores vary across traits

Lehmann

Mackintosh

McVean

et al. 2021

Preprint

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Polygenic scores (PGS) are individual-level measures that quantify the genetic contribution to a given trait. PGS have predominantly been developed using European ancestry samples and recent studies have shown that the predictive performance of European ancestry-derived PGS is lower in non-European ancestry samples, reflecting differences in linkage disequilibrium, variant frequencies, and variant effects across populations. However, the problem of how best to maximize performance within any one ancestry group given the data available, and the extent to which this varies between traits, are largely unexplored. Here, we investigate the effect of sample size and ancestry composition on the predictive performance of PGS for fifteen traits in UK Biobank and evaluate an importance reweighting approach that aims to counteract the under-representation of certain groups within training data. We find that, for a minority of the traits, PGS estimated using a relatively small number of Black/Black British individuals outperformed, on a Black/Black British test set, scores estimated using a much larger number of White individuals. For example, a PGS for mean corpuscular volume trained on only Black individuals achieved a 4-fold improvement on a corresponding PGS trained on only White individuals. For the remainder of the traits, the reverse was true; a PGS for height trained on only Black/Black British individuals explained less than 0.5% of the variance in height in a Black/Black British test set, compared to 3.9% for a PGS trained on a much larger training set consisting of only White individuals. We find that while importance weighting provides moderate benefit for some traits (for example, 40% improvement for mean corpuscular volume compared to no reweighting), the improvement is modest in most cases, arguing that only targeted collection of data from underrepresented groups can address differences in PGS performance.

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“…Summary statistics were downloaded from the NHGRI-EBI GWAS Catalog 82 for the studies GCST007362/GCST007361 83 , GCST001345 84 , GCST000563 85 , GCST007361 83 , GCST007844 86 , GCST001149 87 , GCST005529 88 , GCST008910 89 , GCST003097 90 , and GCST010481 91 downloaded on 04/09/2020.…”

Section: Methodsmentioning

confidence: 99%

Intra-ocular dendritic cells are increased in HLA-B27 associated acute anterior uveitis

Kasper

Heming

Schafflick

et al. 2021

Preprint

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Uveitis describes a heterogeneous group of inflammatory eye diseases characterized by infiltration of leukocytes into the uveal tissues. HLA-B27-associated Uveitis is a common subtype of uveitis and a prototypical ocular autoimmune disease. Local immune mechanisms driving human uveitis are poorly characterized mainly due to the limited available biomaterial and subsequent technical limitations. Here, we provide the first high-resolution characterization of intraocular leukocytes in HLA-B27 positive and negative AU and an infectious endophthalmitis control by combining single cell RNA sequencing (scRNA-seq) with flow cytometry and low-input proteomics. Ocular cell infiltrates consisted primarily of lymphocytes in uveitis and of myeloid cells in infectious endophthalmitis. HLA-B27 positive uveitis exclusively featured an plasmacytoid and classical dendritic cells (cDC) infiltrate, and of plasma cells. Moreover, cDCs were central in predicted local cell-cell communication. The data suggests a unique pattern of ocular leukocyte infiltration in HLA-B27 positive uveitis with relevance of particular dendritic cells.

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Bayesian meta‐analysis across genome‐wide association studies of diverse phenotypes

Cited by 31 publications

References 48 publications

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Optimal strategies for learning multi-ancestry polygenic scores vary across traits

Intra-ocular dendritic cells are increased in HLA-B27 associated acute anterior uveitis

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