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Laura Almasy

Publications and source records attributed to Laura Almasy.

4 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↗
PubMed2025

Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding.

BACKGROUND: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (&#x2264; 50 IU/dL) in the general population is underexplored. OBJECTIVES: To identify genetic variants influencing VWF:Ag levels &#x2264; 50 IU/dL. METHODS: We performed a genome-wide association study in 926 cases with VWF:Ag levels &#x2264; 50 IU/dL and 12 846 controls from 7 studies from the Trans-Omics for Precision Medicine program. We then examined whether significant genome-wide findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1 286 069 controls, and with 6 bleeding and thrombotic disorders in FinnGen. RESULTS: Variants at 2 loci were associated (P < 5 &#xd7; 10-9) with VWF:Ag levels &#x2264; 50 IU/dL: ABO and VWF. The VWF index variant, p.Tyr1584Cys, is a rare (0.22%) missense variant with odds ratio (OR) of 78.58, while the ABO index variant is a common intronic variant with a smaller effect (OR = 2.52). Notably, both VWF (OR = 7.16) and ABO (OR = 1.57) variants were also associated (P < .025) with diagnosed VWD. Among p.Tyr1584Cys heterozygotes, the penetrance of VWF:Ag levels &#x2264; 50 IU/dL was 24.2% and the penetrance of diagnosed VWD was 0.3%. p.Tyr1584Cys was associated (P < .0042) with increased odds of heavy menstrual bleeding (OR = 1.27), iron deficiency anemia (OR = 1.55), and intrapartum hemorrhage (OR = 2.20), but decreased odds of deep vein thrombosis (OR = 0.54). CONCLUSIONS: Although there are currently conflicting interpretations of pathogenicity p.Tyr1584Cys, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels &#x2264; 50 IU/dL, bleeding, and VWD.

Humans↗
PubMed2025

Gene dosage architecture across complex traits.

UNLABELLED: Copy number variants (CNVs) have large effects on complex traits, but they are rare and remain challenging to study. As a result, our understanding of biological functions linking gene dosage to complex traits remains limited, and whether these functions sensitive to gene dosage are similar to those underlying the effects of rare single nucleotide variants (SNVs) and common variants remains unknown. METHODS: We developed FunBurd, a functional burden analysis, to test the association of CNVs aggregated within functional gene sets. We applied this approach in 500,000 individuals from the UK Biobank to associate 43 complex traits with CNVs disrupting 172 gene sets across tissues and cell types. We compared CNV findings with those from common variants and LoF (Loss of Function) SNVs in the same cohort using the same functional gene sets. RESULTS: All 43 traits showed FDR significant associations with CNVs. Brain tissue and neuronal cell-types showed the highest levels of pleiotropy. Most of the functional gene set associations could, in part, be explained by genetic constraint, except for brain related processes. Shared genetic contributions between pairs of traits were concordant across types of variants, but on average 2-fold higher, for rare CNVs and SNVs compared to common variants.Functional enrichment across traits found limited overlap between CNVs and common variants. Moreover, the effects of deletions and duplications were negatively correlated for most traits.In conclusion, we present new methods to separate the contributions of genetic constraint and gene function to the associations of CNVs with complex traits. Overall, the functional convergence between different types of variants -even between deletions and duplications-remains limited.

Journal Article↗