Significance testing for small annotations in stratified LD-Score regression

Tashman, Katherine; R, Cui; O’Connor, Luke J; Neale, Benjamin M.; Hk, Finucane

doi:10.1101/2021.03.13.21249938

Cited by 20 publications

(16 citation statements)

References 12 publications

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“…Finally, stratified LD score regression has elevated false positive rates for small annotations, which may affect our analysis of small gene sets. 31 Despite these limitations, this study presents a novel approach for estimating gene-mediated heritability and informs our understanding of the convergence of common and rare genetic variation. Finally, we have released software for implementing AMM at the command-line.…”

Section: Discussionmentioning

confidence: 99%

“…There was a surprising 8.6x enrichment (SE: 2.7x, P = 2.3e-3) of neuroticism in the diabetes gene set; other brain-related traits were not enriched in this gene set (Supplementary Table 6), and S-LDSC is known to occasionally produce false positives for small annotations (see Discussion). 31 Finally, we analyzed mediated heritability enrichment in 251 genes associated with developmental disorders (mostly neurodevelopmental). We find enrichments for cognitive traits in this gene set, including schizophrenia (3.5x, P = 0.01) and neuroticism (3.5x, P = 0.01).…”

Section: Figure 3 | Snp-to-gene Architecture Of 47 Complex Traits (A)mentioning

confidence: 99%

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Partitioning gene-mediated disease heritability without eQTLs

Weiner

Gazal

et al. 2021

Preprint

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Unknown SNP-to-gene regulatory architecture complicates efforts to link noncoding GWAS associations with genes implicated by sequencing or functional studies. eQTLs are used to link SNPs to genes, but expression in bulk tissue explains a small fraction of disease heritability. A simple but successful approach has been to link SNPs with nearby genes, but the fraction of heritability mediated by these genes is unclear, and gene-proximal (vs. gene-mediated) heritability enrichments are attenuated accordingly. We propose the Abstract Mediation Model (AMM) to estimate (1) the fraction of heritability mediated by the closest or kth-closest gene to each SNP and (2) the mediated heritability enrichment of a gene set (e.g. genes with rare-variant associations). AMM jointly estimates these quantities by matching the decay in SNP enrichment with distance from genes in the gene set. Across 47 complex traits and diseases, we estimate that the closest gene to each SNP mediates 27% (SE: 6%) of heritability, and that a substantial fraction is mediated by genes outside the ten closest. Mendelian disease genes are strongly enriched for common-variant heritability; for example, just 21 dyslipidemia genes mediate 25% of LDL heritability (211x enrichment, P = 0.01). Among brain-related traits, genes involved in neurodevelopmental disorders are only about 4x enriched, but gene expression patterns are highly informative, with detectable differences in per-gene heritability even among weakly brain-expressed genes.

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Section: Discussionmentioning

confidence: 99%

Section: Figure 3 | Snp-to-gene Architecture Of 47 Complex Traits (A)mentioning

confidence: 99%

Partitioning gene-mediated disease heritability without eQTLs

Weiner

Gazal

et al. 2021

Preprint

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“…First, we mapped proteins from the mouse proteome to their corresponding genes using Uniprot Knowledgebase (https:// www.uniprot.org/id-mapping) and converted the mouse genes to their human orthologs using the NCBI HomoloGene database. S-LDSC had primarily been used to analyze enrichment of large gene sets and it was shown that a Type I error is not always controlled in the analysis of small annotations or gene sets 65 . Therefore, we defined two protein sets of the top 1,000 upregulated and 1,000 downregulated proteins in each PSD proteome.…”

Section: Volumetric Brain Mrimentioning

confidence: 99%

Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models

Dejanovic

Wu²,

Tsai³

et al. 2022

Nat Aging

130

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Microglia and complement can mediate neurodegeneration in Alzheimer’s disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in TauP301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in TauP301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte–synapse association and decreased astrocytic and microglial synapses engulfment in TauP301S mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.

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“…Results are shown in table S4, with statistical significance defined as P adj < 0.05. Analyses were performed on both brain-filtered pelvic subelement sets and the smaller specific pelvic subelement sets, although, given issues of sparsity, the results of the latter were not considered reliable (64).…”

Section: Gwas Phenotypic Analysismentioning

confidence: 99%

The developmental impacts of natural selection on human pelvic morphology

et al. 2022

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Evolutionary responses to selection for bipedalism and childbirth have shaped the human pelvis, a structure that differs substantially from that in apes. Morphology related to these factors is present by birth, yet the developmental-genetic mechanisms governing pelvic shape remain largely unknown. Here, we pinpoint and characterize a key gestational window when human-specific pelvic morphology becomes recognizable, as the ilium and the entire pelvis acquire traits essential for human walking and birth. We next use functional genomics to molecularly characterize chondrocytes from different pelvic subelements during this window to reveal their developmental-genetic architectures. We then find notable evidence of ancient selection and genetic constraint on regulatory sequences involved in ilium expansion and growth, findings complemented by our phenotypic analyses showing that variation in iliac traits is reduced in humans compared to African apes. Our datasets provide important resources for musculoskeletal biology and begin to elucidate developmental mechanisms that shape human-specific morphology.

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Significance testing for small annotations in stratified LD-Score regression

Cited by 20 publications

References 12 publications

Partitioning gene-mediated disease heritability without eQTLs

Partitioning gene-mediated disease heritability without eQTLs

Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models

The developmental impacts of natural selection on human pelvic morphology

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