4 research outputs found
Recommended from our members
Common genetic variants contribute to risk of rare severe neurodevelopmental disorders
Most known genetic causes of severe childhood developmental disorders are rare, deleterious, protein-coding changes that cause Mendelian disorders. Children with these disorders typically show early-onset impairment in growth, learning and adaptive behaviours. Linkage and whole exome sequencing studies on these patients have previously focused on identifying diagnostic rare variants that are solely responsible for the patientâs phenotype. In this thesis, I investigate whether common, inherited genetic variation also plays a modifying role in severe, presumably Mendelian neurodevelopmental disorders. In addition, I study the effects of common variants on the cognitive functioning of healthy individuals, who carry rare deleterious variants in genes that are intolerant to such variants in the general population. To test whether common variants contribute to neurodevelopmental disorders that are expected to be almost entirely monogenic, I conduct a genome-wide association study (GWAS) in nearly 7,000 patients from the Deciphering Developmental Disorders (DDD) Study and ancestry-matched controls. I show that common genetic variants explain almost 8% of variation in risk for these severe disorders. I also find genetic overlap between our study and GWAS for other cognitive and neuropsychiatric traits. This suggests that common variants individually have a small effect on brain development and functioning, influencing both risk for common diseases in the population and risk for severe disorders that affect only a small number of individuals. This polygenic burden in the DDD is also not confined to only patients who do not have diagnostic rare variants. Altogether, these results may have important implications for understanding variable clinical presentation of neurodevelopmental disorders and searching for secondary genetic modifiers. Finally, I assess the interplay between common and rare variants on the cognitive functioning of seemingly healthy individuals. Using data from the INTERVAL Study, I test whether common variants are protective of the deleterious rare variants in these individuals. Whilst these analyses are potentially currently underpowered, with additional samples in the future, we may be able to shed more light on expressivity and penetrance of deleterious variants in the general population.Wellcome Trus
Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.Peer reviewe
New insights into the genetic etiology of Alzheimerâs disease and related dementias
Characterization of the genetic landscape of Alzheimerâs disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/âproxyâ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele