Recent work has hinted at the linkage disequilibrium (LD)-dependent architecture of human complex traits, where SNPs with low levels of LD (LLD) have larger per-SNP heritability. Here we analyzed summary statistics from 56 complex traits (average N = 101,401) by extending stratified LD score regression to continuous annotations. We determined that SNPs with low LLD have significantly larger per-SNP heritability and that roughly half of this effect can be explained by functional annotations negatively correlated with LLD, such as DNase I hypersensitivity sites (DHSs). The remaining signal is largely driven by our finding that more recent common variants tend to have lower LLD and to explain more heritability (P = 2.38 × 10-104); the youngest 20% of common SNPs explain 3.9 times more heritability than the oldest 20%, consistent with the action of negative selection. We also inferred jointly significant effects of other LD-related annotations and confirmed via forward simulations that they jointly predict deleterious effects.
Evolution in health and medicine Sackler colloquium: Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies
Family history of psychiatric disorders and the outcome of psychiatric patients with DSM-IV major depressive disorder
Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance
Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
Differential relationship of DNA replication timing to different forms of human mutation and variation
Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
Deleterious alleles in the human genome are on average younger than neutral alleles of the same frequency
Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture
Estimation of complex effect-size distributions using summary-level statistics from genome-wide association studies across 32 complex traits
The accuracy of LD Score regression as an estimator of confounding and genetic correlations in genome-wide association studies
Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types.
Estimation of allele-specific fitness effects across human protein-coding sequences and implications for disease
De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia.
Genome-wide heritability analysis of severe malaria resistance reveals evidence of polygenic inheritance.
Annotations capturing cell type-specific TF binding explain a large fraction of disease heritability.
Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution
Identifying and exploiting trait-relevant tissues with multiple functional annotations in genome-wide association studies
Leveraging molecular quantitative trait loci to understand the genetic architecture of diseases and complex traits
Functional architecture of low-frequency variants highlights strength of negative selection across coding and non-coding annotations
Confounding of linkage disequilibrium patterns in large scale DNA based gene-gene interaction studies
Trans-ancestral dissection of urate- and gout-associated major loci SLC2A9 and ABCG2 reveals primate-specific regulatory effects.
Chromatin interactions and expression quantitative trait loci reveal genetic drivers of multimorbidities
Accurate estimation of SNP-heritability from biobank-scale data irrespective of genetic architecture
Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia.
Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits.
Integrative analysis of Dupuytren's disease identifies novel risk locus and reveals a shared genetic etiology with BMI
Genetic associations of breast and prostate cancer are enriched for regulatory elements identified in disease-related tissues
Liability threshold modeling of case-control status and family history of disease increases association power.
Allergy and Asthma
Allergy and asthma are inflammatory disorders that are triggered by the activation of an allergen-specific regulatory t cell. These t cells become activated when allergens are recognized by allergen-presenting cells. Here is the latest research on allergy and asthma.