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Nature Genetics Aug 2023Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point...
Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.
Topics: Humans; Multifactorial Inheritance; Quantitative Trait Loci; Genome-Wide Association Study; Genetic Predisposition to Disease; Phenotype; Polymorphism, Single Nucleotide
PubMed: 37443254
DOI: 10.1038/s41588-023-01443-6 -
Science (New York, N.Y.) Jul 2023The human skeletal form underlies bipedalism, but the genetic basis of skeletal proportions (SPs) is not well characterized. We applied deep-learning models to 31,221...
The human skeletal form underlies bipedalism, but the genetic basis of skeletal proportions (SPs) is not well characterized. We applied deep-learning models to 31,221 x-rays from the UK Biobank to extract a comprehensive set of SPs, which were associated with 145 independent loci genome-wide. Structural equation modeling suggested that limb proportions exhibited strong genetic sharing but were independent of width and torso proportions. Polygenic score analysis identified specific associations between osteoarthritis and hip and knee SPs. In contrast to other traits, SP loci were enriched in human accelerated regions and in regulatory elements of genes that are differentially expressed between humans and great apes. Combined, our work identifies specific genetic variants that affect the skeletal form and ties a major evolutionary facet of human anatomical change to pathogenesis.
Topics: Humans; Genome-Wide Association Study; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide; Genome, Human; Skeleton; Evolution, Molecular; Male; Female
PubMed: 37471560
DOI: 10.1126/science.adf8009 -
Nature Reviews. Genetics Jan 2024Polygenic risk scores (PRSs) summarize the genetic predisposition of a complex human trait or disease and may become a valuable tool for advancing precision medicine.... (Review)
Review
Polygenic risk scores (PRSs) summarize the genetic predisposition of a complex human trait or disease and may become a valuable tool for advancing precision medicine. However, PRSs that are developed in populations of predominantly European genetic ancestries can increase health disparities due to poor predictive performance in individuals of diverse and complex genetic ancestries. We describe genetic and modifiable risk factors that limit the transferability of PRSs across populations and review the strengths and weaknesses of existing PRS construction methods for diverse ancestries. Developing PRSs that benefit global populations in research and clinical settings provides an opportunity for innovation and is essential for health equity.
Topics: Humans; Genetic Predisposition to Disease; Risk Factors; Multifactorial Inheritance; Precision Medicine; Genome-Wide Association Study
PubMed: 37620596
DOI: 10.1038/s41576-023-00637-2 -
Proceedings of the National Academy of... Aug 2023Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to...
Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having two or more autistic children. Using this study design, we identify seven previously unrecognized ASD risk genes supported by a majority of rare inherited variants, finding support for a total of 74 genes in our cohort and a total of 152 genes after combined analysis with other studies. Autistic children from multiplex families demonstrate an increased burden of rare inherited protein-truncating variants in known ASD risk genes. We also find that ASD polygenic score (PGS) is overtransmitted from nonautistic parents to autistic children who also harbor rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD PGS overtransmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD.
Topics: Child; Humans; Autism Spectrum Disorder; Multifactorial Inheritance; Parents; Whole Genome Sequencing; Language Development Disorders; Genetic Predisposition to Disease
PubMed: 37506195
DOI: 10.1073/pnas.2215632120 -
Medicina Sep 2023Idiopathic generalized epilepsies (IGE) is a group of epilepsies age-dependent, a subgroup of EGG genetic generalized epilepsies, with electro-clinical features and... (Review)
Review
Idiopathic generalized epilepsies (IGE) is a group of epilepsies age-dependent, a subgroup of EGG genetic generalized epilepsies, with electro-clinical features and polygenic inheritance. Four syndromes comprising the IGEs: childhood absence epilepsy (CAD), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and generalized tonic-clonic seizures epilepsy. Clinically characterized by the presence of one or a combination of absence seizures, myoclonus, tonic-clonic, or myoclonictonic- clonic with common electroencephalographic patterns of 2.5-5.5 Hz generalized spike-wave and activated by hyperventilation or photic stimulation. They generally have a good prognosis for seizure control, not evolve to an epileptic encephalopathy. Frequent clinical overlap between the first three, being able to evolve between them; the probability and age of remission varies in each one. About 80% responding to broad-spectrum anti-seizure drugs such as valproic acid, may worsen with sodium or GABAergic blockers. Development is typically normal; however, they are frequently associated with mood disorders, attentiondeficit/ hyperactivity disorder (ADHD), and learning disabilities, but do not have cognitive deficits. The recognition of this group of EGI is important for the adequate use of the resources, avoiding unnecessary studies, adequate orientation of the prognosis and an optimal treatment.
Topics: Humans; Child; Epilepsy, Generalized; Cognition Disorders; Cognitive Dysfunction; Electroencephalography
PubMed: 37714126
DOI: No ID Found -
Nature Communications Dec 2023Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and...
Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and COL4A-associated nephropathy (COL4A-AN) represent the most common forms of monogenic kidney diseases. These disorders have incomplete penetrance and variable expressivity, and we hypothesize that polygenic factors explain some of this variability. By combining SNP array, exome/genome sequence, and electronic health record data from the UK Biobank and All-of-Us cohorts, we demonstrate that the genome-wide polygenic score (GPS) significantly predicts CKD among ADPKD monogenic variant carriers. Compared to the middle tertile of the GPS for noncarriers, ADPKD variant carriers in the top tertile have a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile have only a 3-fold increased risk of CKD. Similarly, the GPS significantly predicts CKD in COL4A-AN carriers. The carriers in the top tertile of the GPS have a 2.5-fold higher risk of CKD, while the risk for carriers in the bottom tertile is not different from the average population risk. These results suggest that accounting for polygenic risk improves risk stratification in monogenic kidney disease.
Topics: Humans; Penetrance; Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic; Multifactorial Inheritance; Risk Factors
PubMed: 38097619
DOI: 10.1038/s41467-023-43878-9 -
Cells Jul 2023Brugada syndrome is a rare hereditary arrhythmia disorder characterized by a distinctive electrocardiogram pattern and an elevated risk of ventricular arrhythmias and... (Review)
Review
Brugada syndrome is a rare hereditary arrhythmia disorder characterized by a distinctive electrocardiogram pattern and an elevated risk of ventricular arrhythmias and sudden cardiac death in young adults. Despite recent advances, it remains a complex condition, encompassing mechanisms, genetics, diagnosis, arrhythmia risk stratification, and management. The underlying electrophysiological mechanism of Brugada syndrome requires further investigation, with current theories focusing on abnormalities in repolarization, depolarization, and current-load match. The genetic basis of the syndrome is strong, with mutations found in genes encoding subunits of cardiac sodium, potassium, and calcium channels, as well as genes involved in channel trafficking and regulation. While the initial discovery of mutations in the SCN5A gene provided valuable insights, Brugada syndrome is now recognized as a multifactorial disease influenced by several loci and environmental factors, challenging the traditional autosomal dominant inheritance model. This comprehensive review aims to provide a current understanding of Brugada syndrome, focusing on its pathophysiology, genetic mechanisms, and novel models of risk stratification. Advancements in these areas hold the potential to facilitate earlier diagnosis, improve risk assessments, and enable more targeted therapeutic interventions.
Topics: Humans; Brugada Syndrome; Death, Sudden, Cardiac; Electrocardiography; Mutation; Risk Assessment
PubMed: 37443825
DOI: 10.3390/cells12131791 -
Nature Medicine Sep 2023Most complex human traits differ by sex, but we have limited insight into the underlying mechanisms. Here, we investigated the influence of biological sex on protein...
Most complex human traits differ by sex, but we have limited insight into the underlying mechanisms. Here, we investigated the influence of biological sex on protein expression and its genetic regulation in 1,277 human brain proteomes. We found that 13.2% (1,354) of brain proteins had sex-differentiated abundance and 1.5% (150) of proteins had sex-biased protein quantitative trait loci (sb-pQTLs). Among genes with sex-biased expression, we found 67% concordance between sex-differentiated protein and transcript levels; however, sex effects on the genetic regulation of expression were more evident at the protein level. Considering 24 psychiatric, neurologic and brain morphologic traits, we found that an average of 25% of their putatively causal genes had sex-differentiated protein abundance and 12 putatively causal proteins had sb-pQTLs. Furthermore, integrating sex-specific pQTLs with sex-stratified genome-wide association studies of six psychiatric and neurologic conditions, we uncovered another 23 proteins contributing to these traits in one sex but not the other. Together, these findings begin to provide insights into mechanisms underlying sex differences in brain protein expression and disease.
Topics: Female; Male; Humans; Sex Characteristics; Genome-Wide Association Study; Brain; Multifactorial Inheritance; Phenotype
PubMed: 37653343
DOI: 10.1038/s41591-023-02509-y -
Genes Aug 2023With the increased availability of genomic sequencing technologies, the molecular bases for kidney diseases such as nephronophthisis and mitochondrially inherited and... (Review)
Review
With the increased availability of genomic sequencing technologies, the molecular bases for kidney diseases such as nephronophthisis and mitochondrially inherited and autosomal-dominant tubulointerstitial kidney diseases (ADTKD) has become increasingly apparent. These tubulointerstitial kidney diseases (TKD) are monogenic diseases of the tubulointerstitium and result in interstitial fibrosis and tubular atrophy (IF/TA). However, monogenic inheritance alone does not adequately explain the highly variable onset of kidney failure and extra-renal manifestations. Phenotypes vary considerably between individuals harbouring the same pathogenic variant in the same putative monogenic gene, even within families sharing common environmental factors. While the extreme end of the disease spectrum may have dramatic syndromic manifestations typically diagnosed in childhood, many patients present a more subtle phenotype with little to differentiate them from many other common forms of non-proteinuric chronic kidney disease (CKD). This review summarises the expanding repertoire of genes underpinning TKD and their known phenotypic manifestations. Furthermore, we collate the growing evidence for a role of modifier genes and discuss the extent to which these data bridge the historical gap between apparently rare monogenic TKD and polygenic non-proteinuric CKD (excluding polycystic kidney disease).
Topics: Humans; Kidney; Polycystic Kidney Diseases; Chromosome Mapping; Genes, Modifier; Renal Insufficiency, Chronic
PubMed: 37628633
DOI: 10.3390/genes14081582