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Brain, Behavior, and Immunity Jul 2024There are inter-individual differences in susceptibility to the influence of early life experiences for which the underlying neurobiological mechanisms are poorly...
There are inter-individual differences in susceptibility to the influence of early life experiences for which the underlying neurobiological mechanisms are poorly understood. Microglia play a role in environmental surveillance and may influence individual susceptibility to environmental factors. As an index of neurodevelopment, we estimated individual slopes of mean white matter fractional anisotropy (WM-FA) across three time-points (age 4.5, 6.0, and 7.5 years) for 351 participants. Individual variation in microglia reactivity was derived from an expression-based polygenic score(ePGS) comprised of Single Nucleotide Polymorphisms (SNPs) functionally related to the expression of microglia-enriched genes.A higher ePGS denotes an increased genetic capacity for the expression of microglia-related genes, and thus may confer a greater capacity to respond to the early environment and to influence brain development. We hypothesized that this ePGS would associate with the WM-FA index of neurodevelopment and moderate the influence of early environmental factors.Our findings show sex dependency, where a significant association between WM-FA and microglia ePGS was only obtained for females.We then examined associations with perinatal factors known to decrease (optimal birth outcomes and familial conditions) or increase (systemic inflammation) the risk for later mental health problems.In females, individuals with high microglia ePGS showed a negative association between systemic inflammation and WM-FA and a positive association between more advantageous environmental conditions and WM-FA. The microglia ePGS in females thus accounted for variations in the influence of the quality of the early environment on WM-FA.Finally, WM-FA slopes mediated the association of microglia ePGS with interpersonal problems and social hostility in females. Our findings suggest the genetic capacity for microglia function as a potential factor underlying differential susceptibility to early life exposuresthrough influences on neurodevelopment.
Topics: Humans; Microglia; Female; Male; White Matter; Polymorphism, Single Nucleotide; Child; Child, Preschool; Brain; Sex Factors; Multifactorial Inheritance
PubMed: 38677627
DOI: 10.1016/j.bbi.2024.04.038 -
Genes Apr 2024Tocopherols are secondary metabolites synthesized through the shikimate biosynthetic pathway in the plastids of most plants. It is well known that α-Tocopherol (vitamin... (Review)
Review
Tocopherols are secondary metabolites synthesized through the shikimate biosynthetic pathway in the plastids of most plants. It is well known that α-Tocopherol (vitamin E) has many health benefits for humans and animals; therefore, it is highly used in human and animal diets. Tocopherols vary considerably in most crop (and plant) species and within cultivars of the same species depending on environmental and growth conditions; tocopherol content is a polygenic, complex traits, and its inheritance is poorly understood. The objective of this review paper was to summarize all identified quantitative trait loci (QTL) that control seed tocopherols and related contents identified in maize () during the past two decades (2002-2022). Candidate genes identified within these QTL regions are also discussed. The QTL described here, and candidate genes identified within these genomic regions could be used in breeding programs to develop maize cultivars with high, beneficial levels of seed tocopherol contents.
Topics: Zea mays; Quantitative Trait Loci; Seeds; Tocopherols
PubMed: 38674406
DOI: 10.3390/genes15040472 -
Genes Apr 2024Familial hypercholesterolemia (FH) comprises high LDL-cholesterol (LDL-c) levels and high cardiovascular disease risk. In the absence of pathogenic variants in causative...
BACKGROUND
Familial hypercholesterolemia (FH) comprises high LDL-cholesterol (LDL-c) levels and high cardiovascular disease risk. In the absence of pathogenic variants in causative genes, a polygenic basis was hypothesized.
METHODS
In a population of 418 patients (excluding homozygotes) with clinical suspicion of FH, the FH-causative genes and the regions of single nucleotide polymorphisms (SNPs) included in 12-SNP and 6-SNP scores were sequenced by next-generation sequencing, allowing for the detection of pathogenic variants (V+) in 220 patients. To make a comparison, only patients without uncertain significance variants (V-/USV-) were considered ( = 162).
RESULTS
Higher values of both scores were observed in V+ than in V-. Considering a cut-off leading to 80% of V-/USV- as score-positive, a lower prevalence of patients positive for both 12-SNP and 6-SNP scores was observed in V+ ( = 0.010 and 0.033, respectively). Mainly for the 12-SNP score, among V+ patients, higher LDL-c levels were observed in score-positive (223 mg/dL -IQR 187-279) than in negative patients (212 mg/dL -IQR 162-240; = 0.006). Multivariate analysis confirmed the association of scores and LDL-c levels independently of age, sex, and presence of pathogenic variants and revealed a greater association in children.
CONCLUSIONS
The 12-SNP and 6-SNP polygenic scores could explain hypercholesterolemia in patients without pathogenic variants as well as the variability of LDL-c levels among patients with FH-causative variants.
Topics: Humans; Hyperlipoproteinemia Type II; Male; Female; Polymorphism, Single Nucleotide; Cholesterol, LDL; Middle Aged; Adult; Genetic Predisposition to Disease; Multifactorial Inheritance; Aged
PubMed: 38674396
DOI: 10.3390/genes15040462 -
Genome Medicine Apr 2024The clinical utility of genetic information for type 2 diabetes (T2D) prediction with polygenic scores (PGS) in ancestrally diverse, real-world US healthcare systems is...
BACKGROUND
The clinical utility of genetic information for type 2 diabetes (T2D) prediction with polygenic scores (PGS) in ancestrally diverse, real-world US healthcare systems is unclear, especially for those at low clinical phenotypic risk for T2D.
METHODS
We tested the association of PGS with T2D incidence in patients followed within a primary care practice network over 16 years in four hypothetical scenarios that varied by clinical data availability (N = 14,712): (1) age and sex; (2) age, sex, body mass index (BMI), systolic blood pressure, and family history of T2D; (3) all variables in (2) and random glucose; and (4) all variables in (3), HDL, total cholesterol, and triglycerides, combined in a clinical risk score (CRS). To determine whether genetic effects differed by baseline clinical risk, we tested for interaction with the CRS.
RESULTS
PGS was associated with incident T2D in all models. Adjusting for age and sex only, the Hazard Ratio (HR) per PGS standard deviation (SD) was 1.76 (95% CI 1.68, 1.84) and the HR of top 5% of PGS vs interquartile range (IQR) was 2.80 (2.39, 3.28). Adjusting for the CRS, the HR per SD was 1.48 (1.40, 1.57) and HR of the top 5% of PGS vs IQR was 2.09 (1.72, 2.55). Genetic effects differed by baseline clinical risk ((PGS-CRS interaction p = 0.05; CRS below the median: HR 1.60 (1.43, 1.79); CRS above the median: HR 1.45 (1.35, 1.55)).
CONCLUSIONS
Genetic information can help identify high-risk patients even among those perceived to be low risk in a clinical evaluation.
Topics: Humans; Diabetes Mellitus, Type 2; Male; Female; Middle Aged; Multifactorial Inheritance; Aged; Incidence; Physicians, Primary Care; Adult; Risk Factors; Genetic Predisposition to Disease; Longitudinal Studies; Primary Health Care; Cohort Studies
PubMed: 38671457
DOI: 10.1186/s13073-024-01337-0 -
Scientific Reports Apr 2024Chronic kidney disease (CKD) is a complex disorder that causes a gradual loss of kidney function, affecting approximately 9.1% of the world's population. Here, we use a...
Chronic kidney disease (CKD) is a complex disorder that causes a gradual loss of kidney function, affecting approximately 9.1% of the world's population. Here, we use a soft-clustering algorithm to deconstruct its genetic heterogeneity. First, we selected 322 CKD-associated independent genetic variants from published genome-wide association studies (GWAS) and added association results for 229 traits from the GWAS catalog. We then applied nonnegative matrix factorization (NMF) to discover overlapping clusters of related traits and variants. We computed cluster-specific polygenic scores and validated each cluster with a phenome-wide association study (PheWAS) on the BioMe biobank (n = 31,701). NMF identified nine clusters that reflect different aspects of CKD, with the top-weighted traits signifying areas such as kidney function, type 2 diabetes (T2D), and body weight. For most clusters, the top-weighted traits were confirmed in the PheWAS analysis. Results were found to be more significant in the cross-ancestry analysis, although significant ancestry-specific associations were also identified. While all alleles were associated with a decreased kidney function, associations with CKD-related diseases (e.g., T2D) were found only for a smaller subset of variants and differed across genetic ancestry groups. Our findings leverage genetics to gain insights into the underlying biology of CKD and investigate population-specific associations.
Topics: Humans; Renal Insufficiency, Chronic; Genome-Wide Association Study; Phenotype; Cluster Analysis; Multifactorial Inheritance; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Algorithms; Diabetes Mellitus, Type 2; Male; Female
PubMed: 38671065
DOI: 10.1038/s41598-024-59747-4 -
Brain, Behavior, and Immunity Jul 2024There is a two-fold higher incidence of depression in females compared to men with recent studies suggesting a role for microglia in conferring this sex-dependent...
There is a two-fold higher incidence of depression in females compared to men with recent studies suggesting a role for microglia in conferring this sex-dependent depression risk. In this study we investigated the nature of this relation. Using GWAS enrichment, gene-set enrichment analysis and Mendelian randomization, we found minimal evidence for a direct relation between genes functionally related to microglia and sex-dependent genetic risk for depression. We then used expression quantitative trait loci and single nucleus RNA-sequencing resources to generate polygenic scores (PGS) representative of individual variation in microglial function in the adult (UK Biobank; N = 54753-72682) and fetal (ALSPAC; N = 1452) periods. The adult microglial PGS moderated the association between BMI (UK Biobank; beta = 0.001, 95 %CI 0.0009 to 0.003, P = 7.74E-6) and financial insecurity (UK Biobank; beta = 0.001, 95 %CI 0.005 to 0.015, P = 2E-4) with depressive symptoms in females. The fetal microglia PGS moderated the association between maternal prenatal depressive symptoms and offspring depressive symptoms at 24 years in females (ALSPAC; beta = 0.04, 95 %CI 0.004 to 0.07, P = 0.03). We found no evidence for an interaction between the microglial PGS and depression risk factors in males. Our results illustrate a role for microglial function in the conferral of sex-dependent depression risk following exposure to a depression risk factor.
Topics: Humans; Microglia; Female; Male; Depression; Adult; Genome-Wide Association Study; Multifactorial Inheritance; Pregnancy; Sex Factors; Genetic Predisposition to Disease; Risk Factors; Quantitative Trait Loci; Gene-Environment Interaction; Young Adult; Prenatal Exposure Delayed Effects; Sex Characteristics; Mendelian Randomization Analysis
PubMed: 38670238
DOI: 10.1016/j.bbi.2024.04.030 -
PLoS Genetics Apr 2024Polygenic scores (PGS) are measures of genetic risk, derived from the results of genome wide association studies (GWAS). Previous work has proposed the coefficient of...
Polygenic scores (PGS) are measures of genetic risk, derived from the results of genome wide association studies (GWAS). Previous work has proposed the coefficient of determination (R2) as an appropriate measure by which to compare PGS performance in a validation dataset. Here we propose correlation-based methods for evaluating PGS performance by adapting previous work which produced a statistical framework and robust test statistics for the comparison of multiple correlation measures in multiple populations. This flexible framework can be extended to a wider variety of hypothesis tests than currently available methods. We assess our proposed method in simulation and demonstrate its utility with two examples, assessing previously developed PGS for low-density lipoprotein cholesterol and height in multiple populations in the All of Us cohort. Finally, we provide an R package 'coranova' with both parametric and nonparametric implementations of the described methods.
Topics: Humans; Multifactorial Inheritance; Genome-Wide Association Study; Cholesterol, LDL; Genetic Predisposition to Disease; Models, Genetic; Polymorphism, Single Nucleotide; Body Height; Computer Simulation; Genetics, Population
PubMed: 38669290
DOI: 10.1371/journal.pgen.1011249 -
Genome Medicine Apr 2024The "missing" heritability of complex traits may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify,...
The "missing" heritability of complex traits may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify, observe, and detect. We propose a new kernel-based method called Latent Interaction Testing (LIT) to screen for genetic interactions that leverages pleiotropy from multiple related traits without requiring the interacting variable to be specified or observed. Using simulated data, we demonstrate that LIT increases power to detect latent genetic interactions compared to univariate methods. We then apply LIT to obesity-related traits in the UK Biobank and detect variants with interactive effects near known obesity-related genes (URL: https://CRAN.R-project.org/package=lit ).
Topics: Humans; Genome-Wide Association Study; Obesity; Epistasis, Genetic; Quantitative Trait, Heritable; Quantitative Trait Loci; Models, Genetic; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Genetic Pleiotropy; Phenotype; Multifactorial Inheritance
PubMed: 38664839
DOI: 10.1186/s13073-024-01329-0 -
Nature Communications Apr 2024Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to... (Meta-Analysis)
Meta-Analysis
Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.
Topics: Humans; DNA-Binding Proteins; Genetic Predisposition to Disease; Genome-Wide Association Study; Gout; Heart Failure; Hypertension; Hyperuricemia; Mendelian Randomization Analysis; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Transcriptome; Uric Acid
PubMed: 38658550
DOI: 10.1038/s41467-024-47805-4 -
Nature Communications Apr 2024Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is...
Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGS) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGS [95%CI, 0.30-0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69-0.88], p = 4.0 × 10) or immunosuppressant (n = 354, HR = 0.61 [0.38-0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44-0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.
Topics: Humans; Leukocyte Count; Male; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Female; Multifactorial Inheritance; Leukopenia; Middle Aged; Aged; Adult; Immunosuppressive Agents
PubMed: 38649760
DOI: 10.1038/s41467-024-47804-5