Biomedical subjects

Emma E M Knowles

Publications and source records attributed to Emma E M Knowles.

3 recordsLinked to original sources

PubMed2026

Determinants of functional burden pleiotropy and gene dosage responses across human traits.

Pleiotropic and monotonic effects of gene dosage are central to understanding comorbidities in developmental pediatric and psychiatric disorders, yet the underlying biological processes are not well characterized. Here we develop a functional burden analysis to investigate the association of all protein-coding copy-number variants, genome-wide, with 43 complex traits in approximately 500,000 UK Biobank participants. We test variant associations disrupting 172 tissue or cell-type gene sets, finding associations for all traits, which we replicate in the All of Us cohort. Functional burden pleiotropy, defined as the number of traits significantly associated with a gene set, correlates with genetic constraint and is higher for brain than non-brain functions, even after normalizing for genetic constraint. Levels of pleiotropy, measured by burden correlation, are similar in deletions and loss-of-function single-nucleotide variants, and higher than in common variants and duplications. Most gene dosage responses are non-monotonic, with deletions and duplications showing same-direction effects, and monotonic responses decrease with genetic constraint. We observe associations between functional gene sets and traits for either deletions or duplications, but rarely both, with negatively correlated effect sizes. Together, these results link genetic constraint and brain-specific mechanisms to the whole-body multimorbidity of neurodevelopmental and psychiatric conditions.

Humans↗

PubMed2026

Evaluating psychosis-specific effects of trauma exposure in early-onset and adult-onset psychosis.

Trauma is a risk factor for early-onset (EOP) and adult-onset (AOP) psychosis and is also associated with other psychiatric diagnoses and poorer fputcomes in the general population. We examined (1) whether trauma effects are specific to psychosis and (2) whether these effects differ between EOP and AOP.Linear regression models evaluated trauma exposure in two samples (EOP: 647 cases, 694 controls; AOP: 162 cases, 230 controls) as a function of psychotic and nonpsychotic psychiatric diagnosis (NPD) status. Parallel models assessed associations between trauma and symptom severity, global functioning, and cognition. Relative to individuals without psychiatric disorders, participants with psychosis and comorbid NPDs reported the greatest trauma exposure (EOP: β = 0.95; AOP: β = 1.1), followed by those with psychosis only (EOP: β = 0.67; AOP: β = 0.41) and NPDs only (EOP: β = 0.47; AOP: β = 0.36). Greater numbers of NPDs were associated with higher trauma exposure regardless of psychosis status (EOP: β = 0.15; AOP: β = 0.24). Trauma was associated with greater symptom severity (EOP: β = 0.13; AOP: β = 0.14) and poorer global functioning (EOP: β = -0.21; AOP: β = -0.13), but not cognition. No psychosis-by-trauma interactions were observed.Psychosis-specific effects were limited to greater trauma exposure, while trauma-related impacts on outcomes were similar across diagnostic groups. Findings were consistent across EOP and AOP. Results highlight the need for trauma-informed care in psychiatry given broad effects that influence disease course and prognosis.

Humans↗

PubMed2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Brain↗