-
JAMA Psychiatry Jul 2023Premenstrual disorders are heritable, clinically heterogenous, with a range of affective spectrum comorbidities. It is unclear whether genetic predispositions to...
IMPORTANCE
Premenstrual disorders are heritable, clinically heterogenous, with a range of affective spectrum comorbidities. It is unclear whether genetic predispositions to affective spectrum disorders or other major psychiatric disorders are associated with symptoms of premenstrual disorders.
OBJECTIVE
To assesss whether symptoms of premenstrual disorders are associated with the genetic liability for major psychiatric disorders, as indexed by polygenic risk scores (PRSs).
DESIGN, SETTING, AND PARTICIPANTS
Women from the Norwegian Mother, Father and Child Cohort Study were included in this genetic association study. PRSs were used to determine whether genetic liability for major depression, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, and autism spectrum disorder were associated with the symptoms of premenstrual disorders, using the PRS for height as a somatic comparator. The sample was recruited across Norway between June 1999 and December 2008, and analyses were performed from July 1 to October 14, 2022.
MAIN OUTCOMES AND MEASURES
The symptoms of premenstrual disorders were assessed at recruitment at week 15 of pregnancy with self-reported severity of depression and irritability before menstruation. Logistic regression was applied to test for the association between the presence of premenstrual disorder symptoms and the PRSs for major psychiatric disorders.
RESULTS
The mean (SD) age of 56 725 women included in the study was 29.0 (4.6) years. Premenstrual disorder symptoms were present in 12 316 of 56 725 participants (21.7%). The symptoms of premenstrual disorders were associated with the PRSs for major depression (β = 0.13; 95% CI, 0.11-0.15; P = 1.21 × 10-36), bipolar disorder (β = 0.07; 95% CI, 0.05-0.09; P = 1.74 × 10-11), attention deficit/hyperactivity disorder (β = 0.07; 95% CI, 0.04-0.09; P = 1.58 × 10-9), schizophrenia (β = 0.11; 95% CI, 0.09-0.13; P = 7.61 × 10-25), and autism spectrum disorder (β = 0.03; 95% CI, 0.01-0.05; P = .02) but not with the PRS for height. The findings were confirmed in a subsample of women without a history of psychiatric diagnosis.
CONCLUSIONS
The results of this genetic association study show that genetic liability for both affective spectrum disorder and major psychiatric disorders was associated with symptoms of premenstrual disorders, indicating that premenstrual disorders have overlapping genetic foundations with major psychiatric disorders.
Topics: Child; Humans; Female; Adult; Cohort Studies; Autism Spectrum Disorder; Bipolar Disorder; Depressive Disorder, Major; Risk Factors; Attention Deficit Disorder with Hyperactivity; Genetic Predisposition to Disease; Multifactorial Inheritance
PubMed: 37163253
DOI: 10.1001/jamapsychiatry.2023.1137 -
Nature Communications Aug 2023Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its... (Meta-Analysis)
Meta-Analysis
Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.
Topics: Humans; Male; Androgens; Binding Sites; Multifactorial Inheritance; Neoplasms, Second Primary; Prostatic Neoplasms; Receptors, Androgen
PubMed: 37612283
DOI: 10.1038/s41467-023-39858-8 -
Schizophrenia Research May 2024Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ∼1% of... (Review)
Review
Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ∼1% of populations across cultures. There have been recent major advancements in our understanding of the genetic architecture of schizophrenia. Both rare, highly penetrant genetic variants as well as common, low-penetrant genetic variants can predispose individuals to schizophrenia and can impact the way people metabolize psychoactive medications used to treat schizophrenia. However, the impact of these findings on the clinical management of schizophrenia remains limited. This review highlights the few places where genetics currently informs schizophrenia management strategies, discusses major limitations, and reviews promising areas of genetics research that are most likely to impact future schizophrenia care. Specifically, I focuss on psychiatric genetic counseling, genetic testing strategies, pharmacogenetics, polygenic risk, and genetics-guided treatment. Lastly, I emphasize important ethical considerations in the clinical use of genetics for schizophrenia management, including the exacerbation of healthcare inequalities and unintended consequences of new genetic technologies.
Topics: Humans; Schizophrenia; Pharmacogenetics; Genetic Testing; Genetic Counseling; Multifactorial Inheritance; Genetic Predisposition to Disease
PubMed: 37813777
DOI: 10.1016/j.schres.2023.09.042 -
Briefings in Bioinformatics Mar 2024Polygenetic Risk Scores are used to evaluate an individual's vulnerability to developing specific diseases or conditions based on their genetic composition, by taking... (Review)
Review
Polygenetic Risk Scores are used to evaluate an individual's vulnerability to developing specific diseases or conditions based on their genetic composition, by taking into account numerous genetic variations. This article provides an overview of the concept of Polygenic Risk Scores (PRS). We elucidate the historical advancements of PRS, their advantages and shortcomings in comparison with other predictive methods, and discuss their conceptual limitations in light of the complexity of biological systems. Furthermore, we provide a survey of published tools for computing PRS and associated resources. The various tools and software packages are categorized based on their technical utility for users or prospective developers. Understanding the array of available tools and their limitations is crucial for accurately assessing and predicting disease risks, facilitating early interventions, and guiding personalized healthcare decisions. Additionally, we also identify potential new avenues for future bioinformatic analyzes and advancements related to PRS.
Topics: Humans; Multifactorial Inheritance; Genetic Predisposition to Disease; Software; Computational Biology; Genome-Wide Association Study; Risk Factors; Risk Assessment; Genetic Risk Score
PubMed: 38770718
DOI: 10.1093/bib/bbae240 -
International Journal of Molecular... Apr 2024Our understanding of rare disease genetics has been shaped by a monogenic disease model. While the traditional monogenic disease model has been successful in identifying... (Review)
Review
Our understanding of rare disease genetics has been shaped by a monogenic disease model. While the traditional monogenic disease model has been successful in identifying numerous disease-associated genes and significantly enlarged our knowledge in the field of human genetics, it has limitations in explaining phenomena like phenotypic variability and reduced penetrance. Widening the perspective beyond Mendelian inheritance has the potential to enable a better understanding of disease complexity in rare disorders. Digenic inheritance is the simplest instance of a non-Mendelian disorder, characterized by the functional interplay of variants in two disease-contributing genes. Known digenic disease causes show a range of pathomechanisms underlying digenic interplay, including direct and indirect gene product interactions as well as epigenetic modifications. This review aims to systematically explore the background of digenic inheritance in rare disorders, the approaches and challenges when investigating digenic inheritance, and the current evidence for digenic inheritance in mitochondrial disorders.
Topics: Humans; Mitochondrial Diseases; Rare Diseases; Genetic Predisposition to Disease; Epigenesis, Genetic; Multifactorial Inheritance; Animals
PubMed: 38731822
DOI: 10.3390/ijms25094602 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Nov 2023Thyroid-associated ophthalmopathy (TAO) is a multifactorial-mediated autoimmune orbital disease with the highest incidence of orbital disease in adults. Due to the...
Thyroid-associated ophthalmopathy (TAO) is a multifactorial-mediated autoimmune orbital disease with the highest incidence of orbital disease in adults. Due to the complex clinical manifestations and prolonged course,TAO seriously affect the physical and mental health of patients.The pathogenesis of TAO has not been fully elucidated and the treatment lacks specificity. Therefore, in-depth research on the pathogenesis of TAO is to find effective treatments. In recent years, studies have suggested that there is gut microbiota disorder in TAO, and the risk factors of TAO can promote gut microbiota disorder. Disordered gut microbiota can participate in the occurrence and development of TAO via influencing T cell differentiation, mimicking autoantigens, and influencing host non-coding RNA expression. Modulating the gut microbiota also has therapeutic effects on TAO and is a promising therapeutic approach.
Topics: Adult; Humans; Graves Ophthalmopathy; Gastrointestinal Microbiome; Orbital Diseases; Autoimmune Diseases; Cell Differentiation
PubMed: 38432867
DOI: 10.11817/j.issn.1672-7347.2023.230187 -
Journal of Nephrology Jan 2024Kidney function is strongly influenced by genetic factors with both monogenic and polygenic factors contributing to kidney function. Monogenic disorders with primarily... (Review)
Review
Kidney function is strongly influenced by genetic factors with both monogenic and polygenic factors contributing to kidney function. Monogenic disorders with primarily autosomal dominant inheritance patterns account for 10% of adult and 50% of paediatric kidney diseases. However, kidney function is also a complex trait with polygenic architecture, where genetic factors interact with environment and lifestyle factors. Family studies suggest that kidney function has significant heritability at 35-69%, capturing complexities of the genome with shared environmental factors. Genome-wide association studies estimate the single nucleotide polymorphism-based heritability of kidney function between 7.1 and 20.3%. These heritability estimates, measuring the extent to which genetic variation contributes to CKD risk, indicate a strong genetic contribution. Polygenic Risk Scores have recently been developed for chronic kidney disease and kidney function, and validated in large populations. Polygenic Risk Scores show correlation with kidney function but lack the specificity to predict individual-level changes in kidney function. Certain kidney diseases, such as membranous nephropathy and IgA nephropathy that have significant genetic components, may benefit most from polygenic risk scores for improved risk stratification. Genetic studies of kidney function also provide a potential avenue for the development of more targeted therapies and interventions. Understanding the development and validation of genomic scores is required to guide their implementation and identify the most appropriate potential implications in clinical practice. In this review, we provide an overview of the heritability of kidney function traits in population studies, explore both monogenic and polygenic concepts in kidney disease, with a focus on recently developed polygenic risk scores in kidney function and chronic kidney disease, and review specific diseases which are most amenable to incorporation of genomic scores.
Topics: Adult; Child; Humans; Multifactorial Inheritance; Genome-Wide Association Study; Phenotype; Genetic Risk Score; Renal Insufficiency, Chronic; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide
PubMed: 37989975
DOI: 10.1007/s40620-023-01804-8 -
Nature Communications Oct 2023Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted...
Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.
Topics: Humans; Ethnicity; Genome-Wide Association Study; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Risk Factors; Multifactorial Inheritance; Colorectal Neoplasms
PubMed: 37783704
DOI: 10.1038/s41467-023-41819-0 -
Genome Medicine Feb 2024Polygenic scores (PGS) can be used for risk stratification by quantifying individuals' genetic predisposition to disease, and many potentially clinically useful... (Review)
Review
Polygenic scores (PGS) can be used for risk stratification by quantifying individuals' genetic predisposition to disease, and many potentially clinically useful applications have been proposed. Here, we review the latest potential benefits of PGS in the clinic and challenges to implementation. PGS could augment risk stratification through combined use with traditional risk factors (demographics, disease-specific risk factors, family history, etc.), to support diagnostic pathways, to predict groups with therapeutic benefits, and to increase the efficiency of clinical trials. However, there exist challenges to maximizing the clinical utility of PGS, including FAIR (Findable, Accessible, Interoperable, and Reusable) use and standardized sharing of the genomic data needed to develop and recalculate PGS, the equitable performance of PGS across populations and ancestries, the generation of robust and reproducible PGS calculations, and the responsible communication and interpretation of results. We outline how these challenges may be overcome analytically and with more diverse data as well as highlight sustained community efforts to achieve equitable, impactful, and responsible use of PGS in healthcare.
Topics: Humans; Communication; Genetic Predisposition to Disease; Genomics; Multifactorial Inheritance; Risk Factors; Genome-Wide Association Study
PubMed: 38373998
DOI: 10.1186/s13073-024-01304-9 -
European Archives of Psychiatry and... Dec 2023Schizophrenia (SZ) is a complex disorder with a highly polygenic inheritance. It can be conceived as the extreme expression of a continuum of traits that are present in...
Schizophrenia (SZ) is a complex disorder with a highly polygenic inheritance. It can be conceived as the extreme expression of a continuum of traits that are present in the general population often broadly referred to as schizotypy. However, it is still poorly understood how these traits overlap genetically with the disorder. We investigated whether polygenic risk for SZ is associated with these disorder-related phenotypes (schizotypy, psychotic-like experiences, and subclinical psychopathology) in a sample of 253 non-clinically identified participants. Polygenic risk scores (PRSs) were constructed based on the latest SZ genome-wide association study using the PRS-CS method. Their association with self-report and interview measures of SZ-related traits was tested. No association with either schizotypy or psychotic-like experiences was found. However, we identified a significant association with the Motor Change subscale of the Comprehensive Assessment of At-Risk Mental States (CAARMS) interview. Our results indicate that the genetic overlap of SZ with schizotypy and psychotic-like experiences is less robust than previously hypothesized. The relationship between high PRS for SZ and motor abnormalities could reflect neurodevelopmental processes associated with psychosis proneness and SZ.
Topics: Humans; Schizophrenia; Genome-Wide Association Study; Genetic Predisposition to Disease; Psychotic Disorders; Multifactorial Inheritance
PubMed: 37301774
DOI: 10.1007/s00406-023-01633-7