Biomedical subjects

Guy Hindley

Publications and source records attributed to Guy Hindley.

3 recordsLinked to original sources

PubMed2026

Beyond exons: Linking noncoding heritability and polygenicity across complex human traits and disorders.

The genetic architecture of complex traits spans a continuum of polygenicity, yet it remains unclear how differences in polygenicity relate to the functional localization of SNP heritability across the genome. We use a MiXeR-based framework to partition heritability across 74 functional annotations covering exonic, intronic, and intergenic regions for 34 complex traits and introduce a likelihood-based annotation contribution score that quantifies annotation-specific impact on heritability. Exons account for a minority of heritability, and their contribution decreases with increasing polygenicity, from an average of 22% in less-polygenic somatic diseases and biomarkers to 13% in highly polygenic psychiatric and cognitive phenotypes. Intergenic fractions show the opposite trend, whereas intronic fractions remain relatively stable. Analysis of the broader set of functional annotations also reveals systematic differences along the polygenicity axis: highly polygenic traits show stronger contributions from comparative genomics and variant-effect scores, whereas less-polygenic traits show stronger contributions from promoter, transcription, and chromatin annotations. Together, these results indicate that the functional partitioning of heritability systematically varies with polygenicity, shifting from gene-proximal regulatory architectures to architectures shaped by numerous dispersed regulatory effects.

MiXeR↗

PubMed2026

Beyond Exons: Linking Noncoding Heritability and Polygenicity across Complex Human Traits and Disorders.

The genetic architecture of complex traits spans a continuum of polygenicity, yet it remains unclear how differences in polygenicity relate to the functional localization of SNP heritability across the genome. We use a MiXeR-based framework to partition heritability across exonic, intronic, and intergenic regions for 34 traits and introduce a likelihood-based annotation contribution score that quantifies annotation-specific impact on heritability. Exons explain a minority of heritability, and their contribution decreases with increasing polygenicity, from an average of 22% in less polygenic somatic diseases and biomarkers to 13% in highly polygenic psychiatric and cognitive phenotypes. Intergenic fractions show the opposite trend, whereas intronic fractions remain relatively stable. Analysis of a broader set of functional annotations reveals systematic differences along the polygenicity axis: highly polygenic traits show stronger contributions from comparative genomics and variant-effect scores, whereas less polygenic traits show stronger contributions in promoter, transcription, and chromatin annotations. Together, these results indicate that the functional partitioning of heritability systematically varies with polygenicity, pointing to a shift from gene-proximal regulatory architectures to architectures shaped by numerous dispersed regulatory effects as a key determinant of differences in polygenicity across traits.

Journal Article↗

PubMed2025

Comorbidity alters the genetic relationship between anxiety disorders and major depression.

BACKGROUND: Comorbid anxiety disorders (ANX) and major depression (MD) have worse clinical outcomes than either disorder alone. Analysis of genomic data based on comorbidity status may reveal more precise biological pathways and causal relationships with potential clinical implications. We investigated the genetic relationship between ANX and MD with and without mutual comorbidity. METHODS: We leveraged data from UK Biobank to perform disorder-specific genome-wide association studies (GWAS) of ANX-only (n=189,422) and MD-only (n=194,339) and generate polygenic risk scores (PRS). The Norwegian Mother, Father, and Child Cohort (MoBa, n = 130,992) served to test the associations of PRS with diagnoses. MD and ANX GWAS, including comorbidities (MD-comorbid and ANX-comorbid), were used for comparison. Genetic correlations were compared by comorbidity status, and Mendelian randomization was employed to assess causal relationships. RESULTS: The MD-only PRS showed a stronger association with MD-only compared to ANX-only cases (Z=3.74; Padjusted=0.002); however, MD-comorbid PRS did not show a significant difference (Z=2.71; Padjusted=0.08). The genetic correlation between ANX-only and MD-only was 0.53, lower than between ANX-comorbid and MD-comorbid (0.90). ANX-only showed a causal relationship with MD-only (Padjusted=0.015), but not vice versa, and contrasted the bidirectional causal relationship (Padjusted=2.9e-12, and Padjusted=9.3e-06) when comorbidity was included. Gene sets of MD-comorbid, ANX-comorbid, and MD-only, but not of ANX-only, were enriched for immune regulation pathways such as interleukin production. CONCLUSIONS: ANX and MD show more distinct genetics when comorbid cases are excluded, and ANX may be causal for MD. Disorder-specific genetic studies help uncover more relevant biological mechanisms and guide tailored clinical interventions.

Journal Article↗