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The Lancet. Psychiatry Aug 2023Current definitions and clinical heterogeneity in bipolar disorder are major concerns as they obstruct aetiological research and impede drug development. Therefore,...
BACKGROUND
Current definitions and clinical heterogeneity in bipolar disorder are major concerns as they obstruct aetiological research and impede drug development. Therefore, stratification of bipolar disorder is a high priority. To inform stratification, our analysis aimed to examine the patterns and relationships between polygenic liability for bipolar disorder, major depressive disorder (MDD), and schizophrenia with multidimensional symptom representations of bipolar disorder.
METHODS
In this analysis, data from the UK Bipolar Disorder Research Network (BDRN) were assessed with the Operational Checklist for Psychotic Disorders. Individuals with bipolar disorder as defined in DSM-IV, of European ancestry (self-reported), aged 18 years or older at time of interview, living in the UK, and registered with the BDRN were eligible for inclusion. Psychopathological variables obtained via interview by trained research psychologists or psychiatrists and psychiatric case notes were used to identify statistically distinct symptom dimensions, calibrated with exploratory factor analysis and validated with confirmatory factor analysis (CFA). CFA was extended to include three polygenic risk scores (PRSs) indexing liability for bipolar disorder, MDD, and schizophrenia in a multiple indicator multiple cause (MIMIC) structural equation model to estimate PRS relationships with symptom dimensions.
FINDINGS
Of 4198 individuals potentially eligible for inclusion, 4148 (2804 [67·6%] female individuals and 1344 [32·4%] male individuals) with a mean age at interview of 45 years (SD 12·03) were available for analysis. Three reliable dimensions (mania, depression, and psychosis) were identified. The MIMIC model fitted the data well (root mean square error of approximation 0·021, 90% CI 0·019-0·023; comparative fit index 0·99) and suggests statistically distinct symptom dimensions also have distinct polygenic profiles. The PRS for MDD was strongly associated with the depression dimension (standardised β 0·125, 95% CI 0·080-0·171) and the PRS for schizophrenia was strongly associated with the psychosis dimension (0·108, 0·082-0·175). For the mania dimension, the PRS for bipolar disorder was weakly associated (0·050, 0·002-0·097).
INTERPRETATION
Our findings support the hypothesis that genetic heterogeneity underpins clinical heterogeneity, suggesting that different symptom dimensions within bipolar disorder have partly distinct causes. Furthermore, our results suggest that a specific symptom dimension has a similar cause regardless of the primary psychiatric diagnosis, supporting the use of symptom dimensions in precision psychiatry.
FUNDING
Wellcome Trust and UK Medical Research Council.
Topics: Humans; Male; Female; Middle Aged; Bipolar Disorder; Depressive Disorder, Major; Mania; Psychotic Disorders; United Kingdom; Multifactorial Inheritance; Genetic Predisposition to Disease
PubMed: 37437579
DOI: 10.1016/S2215-0366(23)00186-4 -
Genes Jul 2023Prostate cancer (PC) is polygenic disease involving many genes, and more importantly a host of gene-gene interactions, including transcriptional factors. The gene is a...
Prostate cancer (PC) is polygenic disease involving many genes, and more importantly a host of gene-gene interactions, including transcriptional factors. The gene is a transcriptional target of numerous oncoproteins, and its dysregulation can contribute to tumor progression by abnormal activation of targeted oncogenes. Using data from the Cancer Genome Atlas, we tested the possible involvement of in PC progression. A multi-dimensional scaling (MDS) model was applied to clarify the association of expression with other key genes, such as , , ( and ), , and . An increased expression was associated with higher PC grades and with a worse prognosis. It was also positively related to , , and . Moreover, MDS showed the central role of in influencing the other target genes by its central location on the map. Our study is the first to show a link between expression and other genes involved in PC progression, suggesting a novel role for in PC progression. This network between and through may have an important role in PC progression, as suggested by the association between high expression and unfavorable prognosis in our analysis.
Topics: Male; Humans; Prostatic Neoplasms; Prostate; Oncogenes; Epistasis, Genetic; Multifactorial Inheritance; Intracellular Signaling Peptides and Proteins
PubMed: 37628609
DOI: 10.3390/genes14081558 -
G3 (Bethesda, Md.) Aug 2023Large-effect loci-those statistically significant loci discovered by genome-wide association studies or linkage mapping-associated with key traits segregate amidst a...
Large-effect loci-those statistically significant loci discovered by genome-wide association studies or linkage mapping-associated with key traits segregate amidst a background of minor, often undetectable, genetic effects in wild and domesticated plants and animals. Accurately attributing mean differences and variance explained to the correct components in the linear mixed model analysis is vital for selecting superior progeny and parents in plant and animal breeding, gene therapy, and medical genetics in humans. Marker-assisted prediction and its successor, genomic prediction, have many advantages for selecting superior individuals and understanding disease risk. However, these two approaches are less often integrated to study complex traits with different genetic architectures. This simulation study demonstrates that the average semivariance can be applied to models incorporating Mendelian, oligogenic, and polygenic terms simultaneously and yields accurate estimates of the variance explained for all relevant variables. Our previous research focused on large-effect loci and polygenic variance separately. This work aims to synthesize and expand the average semivariance framework to various genetic architectures and the corresponding mixed models. This framework independently accounts for the effects of large-effect loci and the polygenic genetic background and is universally applicable to genetics studies in humans, plants, animals, and microbes.
Topics: Humans; Animals; Multifactorial Inheritance; Genome-Wide Association Study; Chromosome Mapping; Genome; Phenotype; Models, Genetic; Polymorphism, Single Nucleotide
PubMed: 37405459
DOI: 10.1093/g3journal/jkad148 -
Journal of Medical Genetics Nov 2023Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been...
BACKGROUND
Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.
METHODS
We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.
RESULTS
In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).
CONCLUSIONS
Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
Topics: Humans; Female; Breast Neoplasms; Genome-Wide Association Study; Jews; Israel; Genetic Predisposition to Disease; Risk Factors; Multifactorial Inheritance; Transcription Factors
PubMed: 37451831
DOI: 10.1136/jmg-2023-109185 -
Molecular Psychiatry Oct 2023Deficits in effective executive function, including inhibitory control are associated with risk for a number of psychiatric disorders and significantly impact everyday... (Meta-Analysis)
Meta-Analysis
Deficits in effective executive function, including inhibitory control are associated with risk for a number of psychiatric disorders and significantly impact everyday functioning. These complex traits have been proposed to serve as endophenotypes, however, their genetic architecture is not yet well understood. To identify the common genetic variation associated with inhibitory control in the general population we performed the first trans-ancestry genome wide association study (GWAS) combining data across 8 sites and four ancestries (N = 14,877) using cognitive traits derived from the stop-signal task, namely - go reaction time (GoRT), go reaction time variability (GoRT SD) and stop signal reaction time (SSRT). Although we did not identify genome wide significant associations for any of the three traits, GoRT SD and SSRT demonstrated significant and similar SNP heritability of 8.2%, indicative of an influence of genetic factors. Power analyses demonstrated that the number of common causal variants contributing to the heritability of these phenotypes is relatively high and larger sample sizes are necessary to robustly identify associations. In Europeans, the polygenic risk for ADHD was significantly associated with GoRT SD and the polygenic risk for schizophrenia was associated with GoRT, while in East Asians polygenic risk for schizophrenia was associated with SSRT. These results support the potential of executive function measures as endophenotypes of neuropsychiatric disorders. Together these findings provide the first evidence indicating the influence of common genetic variation in the genetic architecture of inhibitory control quantified using objective behavioural traits derived from the stop-signal task.
Topics: Humans; Genome-Wide Association Study; Schizophrenia; Executive Function; Multifactorial Inheritance; Endophenotypes; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 37500827
DOI: 10.1038/s41380-023-02187-9 -
Asian Journal of Urology Apr 2024Urolithiasis formation has been attributed to environmental and dietary factors. However, evidence is accumulating that genetic background can contribute to urolithiasis... (Review)
Review
OBJECTIVE
Urolithiasis formation has been attributed to environmental and dietary factors. However, evidence is accumulating that genetic background can contribute to urolithiasis formation. Advancements in the identification of monogenic causes using high-throughput sequencing technologies have shown that urolithiasis has a strong heritable component.
METHODS
This review describes monogenic factors implicated in a genetic predisposition to urolithiasis. Peer-reviewed journals were evaluated by a PubMed search until July 2023 to summarize disorders associated with monogenic traits, and discuss clinical implications of identification of patients genetically susceptible to urolithiasis formation.
RESULTS
Given that more than 80% of urolithiases cases are associated with calcium accumulation, studies have focused mainly on monogenetic contributors to hypercalciuric urolithiases, leading to the identification of receptors, channels, and transporters involved in the regulation of calcium renal tubular reabsorption. Nevertheless, available candidate genes and linkage methods have a low resolution for evaluation of the effects of genetic components versus those of environmental, dietary, and hormonal factors, and genotypes remain undetermined in the majority of urolithiasis formers.
CONCLUSION
The pathophysiology underlying urolithiasis formation is complex and multifactorial, but evidence strongly suggests the existence of numerous monogenic causes of urolithiasis in humans.
PubMed: 38680588
DOI: 10.1016/j.ajur.2023.03.004 -
Kidney International Reports May 2024Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite... (Review)
Review
Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite an established genotype-phenotype correlation in cystic kidney diseases, incomplete penetrance and variable disease expressivity are present as is the case in all monogenic diseases. In family members with autosomal dominant polycystic kidney disease (ADPKD), the same causal variant is responsible in all affected family members; however, there can still be striking discordance in phenotype severity. This narrative review explores contributors to within-family discordance in ADPKD severity. Cases of biallelic and digenic inheritance, where 2 rare pathogenic variants in cystogenic genes are coexistent in one family, account for a small proportion of within-family discordance. Genetic background, including cis and trans factors and the polygenic propensity for comorbid disease, also plays a role but has not yet been exhaustively quantified. Environmental exposures, including diet; smoking; alcohol, salt, and protein intake, and comorbid diseases, including obesity, diabetes, hypertension, kidney stones, dyslipidemia, and additional coexistent kidney diseases all contribute to ADPKD phenotypic variability among family members. Given that many of the factors contributing to phenotype variability are preventable, modifiable, or treatable, health care providers and patients need to be aware of these factors and address them in the treatment of ADPKD.
PubMed: 38707833
DOI: 10.1016/j.ekir.2024.01.053 -
Nature Genetics Dec 2023Biobanks often contain several phenotypes relevant to diseases such as major depressive disorder (MDD), with partly distinct genetic architectures. Researchers face...
Biobanks often contain several phenotypes relevant to diseases such as major depressive disorder (MDD), with partly distinct genetic architectures. Researchers face complex tradeoffs between shallow (large sample size, low specificity/sensitivity) and deep (small sample size, high specificity/sensitivity) phenotypes, and the optimal choices are often unclear. Here we propose to integrate these phenotypes to combine the benefits of each. We use phenotype imputation to integrate information across hundreds of MDD-relevant phenotypes, which significantly increases genome-wide association study (GWAS) power and polygenic risk score (PRS) prediction accuracy of the deepest available MDD phenotype in UK Biobank, LifetimeMDD. We demonstrate that imputation preserves specificity in its genetic architecture using a novel PRS-based pleiotropy metric. We further find that integration via summary statistics also enhances GWAS power and PRS predictions, but can introduce nonspecific genetic effects depending on input. Our work provides a simple and scalable approach to improve genetic studies in large biobanks by integrating shallow and deep phenotypes.
Topics: Humans; Depressive Disorder, Major; Genetic Predisposition to Disease; Biological Specimen Banks; Genome-Wide Association Study; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide
PubMed: 37985818
DOI: 10.1038/s41588-023-01559-9 -
Nature Genetics May 2024Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals...
Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.
Topics: Female; Humans; Male; Blood Pressure; Genetic Predisposition to Disease; Genetic Risk Score; Genome-Wide Association Study; Hypertension; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 38689001
DOI: 10.1038/s41588-024-01714-w