Genetic Influences Research Articles

Confounding Fuels Misinterpretation in Human Genetics.

The scientific literature has seen a resurgence of interest in genetic influences on human behavior and socioeconomic outcomes. Such studies face the central difficulty of distinguishing possible causal influences, in particular genetic and non-genetic ones. When confounding between possible influences is not rigorously addressed, it invites over- and misinterpretation of data. We illustrate the breadth of this problem through a discussion of the literature and a reanalysis of two examples. Clark (2023) suggested that patterns of similarity in social status between relatives indicate that social status is largely determined by one's DNA. We show that the paper's conclusions are based on the conflation of genetic and non-genetic transmission, such as wealth, within families. Song & Zhang (2024) posited that genetic variants underlying bisexual behavior are maintained in the population because they also affect risk-taking behavior, thereby conferring an evolutionary fitness advantage through increased sexual promiscuity. In this case, too, we show that possible explanations cannot be distinguished, but only one is chosen and presented as a conclusion. We discuss how issues of confounding apply more broadly to studies that claim to establish genetic underpinnings to human behavior and societal outcomes.

Development of temperament types from infancy to adolescence: Genetic and environmental influences with an economically and racially/ethnically diverse sample.

Kagan theorized biologically based temperament types that are present in infancy, stable across development, and essential for understanding individual differences. Despite evidence, temperament research remains focused on a few prominent dimensions of temperament, without adequately addressing covariance among dimensions and temperament types. Using longitudinal twin data, we took a person-centered statistical approach to identify temperament types and examined continuity and change across five developmental periods (Ninfancy = 602; Ntoddlerhood = 522; Nearly childhood = 390; Nlate childhood = 718; Nearly adolescence = 700). We then examined the genetic and environmental etiology of temperament types. Twins were boys and girls (51-53% female), primarily Hispanic/Latinx (23-30%) and non-Hispanic/Latinx White (56-63%), and from socioeconomically diverse families (28-38% near-or-below the poverty line). Using latent profile analysis, we identified three temperament types at each age characterized by negative reactivity and dysregulation, positive reactivity and strong self-regulation, and moderate reactivity and regulation. Latent transition analyses revealed considerable continuity in membership type for "negative dysregulated" beginning in infancy, log odds = 1.58 (SE = .65) to 3.16 (SE = .77), p < .01, of remaining relative to transitioning to "typical expressive", and "positive well-regulated" beginning in early childhood, log odds = 1.41 (SE = .56) to 2.25 (SE = .47), p < .05. Twin analyses revealed moderate heritability and a consistent role of the shared environment on positive well-regulated, with negative dysregulated and typical expressive also moderately heritable with the shared environment being important at some ages. Findings support the presence of theorized biologically based temperament types that develop rapidly in infancy and toddlerhood and provide a foundation for the study of individual differences and risk and resilience processes across the lifespan. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Role of Vitamin D Metabolism Genes and Their Genomic Background in Shaping Cyclosporine A Dosage Parameters after Kidney Transplantation.

Background: Kidney transplantation is followed by immunosuppressive therapy involving calcineurin inhibitors (CNIs) such as cyclosporin A. However, long-term high CNIs doses can lead to vitamin D deficiency, and genetic variations influencing vitamin D levels can indirectly impact the necessary CNIs dosage. This study investigates the impact of genetic variations of vitamin D binding protein (DBP) rs2282679 and CYP2R1 hydroxylase rs10741657 polymorphisms on the cyclosporin A dosage in kidney transplant recipients. Additional polymorphisims of genes that are predicted to influence the pharmacogenetic profile were included. Methods: Gene polymorphisms in 177 kidney transplant recipients were analyzed using data mining techniques, including the Random Forest algorithm and Classification and Regression Trees (C&RT). The relationship between the concentration/dose (C/D) ratio of cyclosporin A and genetic profiles was assessed to determine the predictive value of DBP rs2282679 and CYP2R1 rs10741657 polymorphisms. Results: Polymorphic variants of the DBP (rs2282679) demonstrated a strong predictive value for the cyclosporin A C/D ratio in post-kidney transplantation patients. By contrast, the CYP2R1 polymorphism (rs10741657) did not show predictive significance. Additionally, the immune response genes rs231775 CTLA4 and rs1800896 IL10 were identified as predictors of cyclosporin A response, though these did not result in statistically significant differences. Conclusions:DBP rs2282679 polymorphisms can significantly predict the cyclosporin A C/D ratio, potentially enhancing the accuracy of CNI dosing. This can help identify patient groups at risk of vitamin D deficiency, ultimately improving the management of kidney transplant recipients. Understanding these genetic influences allows for more personalized and effective treatment strategies, contributing to better long-term outcomes for patients.

Genomic structural variations link multiple genes to bone mineral density in a multi-ethnic cohort study: Louisiana osteoporosis study.

Osteoporosis, characterized by low BMD, is a highly heritable metabolic bone disorder. Although single nucleotide variations (SNVs) have been extensively studied, they explain only a fraction of BMD heritability. Although genomic structural variations (SVs) are large-scale genomic alterations that contribute to genetic diversity in shaping phenotypic variations, the role of SVs in osteoporosis susceptibility remains poorly understood. This study aims to identify and prioritize genes that harbor BMD-related SVs. We performed whole genome sequencing on 4982 subjects from the Louisiana Osteoporosis Study. To obtain high-confidence SVs, the detection of SVs was performed using an ensemble approach. The SVs were tested for association with BMD variation at the hip (HIP), femoral neck (FNK), and lumbar spine (SPN), respectively. Additionally, we conducted co-occurrence analysis using multi-omics approaches to prioritize the identified genes based on their functional importance. Stratification was employed to explore the sex- and ethnicity-specific effects. We identified significant SV-BMD associations: 125 for FNK-BMD, 99 for SPN-BMD, and 83 for HIP-BMD. We observed SVs that were commonly associated with both FNK and HIP BMDs in our combined and stratified analyses. These SVs explain 13.3% to 19.1% of BMD variation. Novel bone-related genes emerged, including LINC02370, ZNF family genes, and ZDHHC family genes. Additionally, FMN2, carrying BMD-related deletions, showed associations with FNK or HIP BMDs, with sex-specific effects. The co-occurrence analysis prioritized an RNA gene LINC00494 and ZNF family genes positively associated with BMDs at different skeletal sites. Two potential causal genes, IBSP and SPP1, for osteoporosis were also identified. Our study uncovers new insights into genetic factors influencing BMD through SV analysis. We highlight BMD-related SVs, revealing a mix of shared and specific genetic influences across skeletal sites and gender or ethnicity. These findings suggest potential roles in osteoporosis pathophysiology, opening avenues for further research and therapeutic targets.

Statistics in Personalized Medicine: Challenges and Innovations

Personalized medicine represents a paradigm shift in healthcare, aiming to tailor medical treatments to individual patients based on their unique genetic profiles, lifestyle factors, and environmental influences. At the forefront of this transformation lies statistics, which plays a pivotal role in integrating diverse data sources, identifying biomarkers, and developing predictive models that guide personalized treatment decisions. However, statistics in personalized medicine face challenges such as data integration complexities, small sample sizes, and ethical considerations. Despite these challenges, innovative statistical approaches including machine learning, Bayesian inference, and multi-omics integration are driving advancements. The future of statistics in personalized medicine lies in integrating multi-omics data, adopting artificial intelligence for predictive modeling, enhancing quantitative pharmacology, leveraging real-world evidence, and addressing ethical and regulatory frameworks. By advancing these fronts, statistics holds the promise to optimize treatment outcomes, improve patient care, and redefine the landscape of healthcare delivery in the 21st century. Keywords: Personalized medicine, Statistics, Data integration, Machine learning, Ethical considerations

The etiology of the association between parental nurturance and youth antisocial behavior: Evidence from a twin differences study

AbstractBackgroundLower parental nurturance is consistently associated with higher levels of youth antisocial behavior (ASB), but the etiology of this association remains unclear. To fill this gap, we employed a twin differences approach to illuminate the environmental and genetic origins of the association between parental nurturance and children's ASB.MethodsParticipants were 2060 twins (49% female) ages 6–10 from the Michigan State University Twin Registry. Parental nurturance and youth ASB were assessed using multiple measures (e.g., questionnaires, interviews) and informant reports (e.g., twins, parents, teachers). Co‐twin difference‐score correlations were analyzed separately by zygosity using specification curve analysis, an exhaustive modeling approach that examined associations across all possible specifications of the nurturance and ASB data.ResultsParental nurturance demonstrated clear, negatively signed associations with youth ASB at the individual level. However, these associations generally did not persist within twin pairs. We observed no significant twin difference correlations within monozygotic (MZ) pairs and only a handful of significant twin difference correlations among dizygotic (DZ) pairs, in which the DZ co‐twin who experienced more nurturance exhibited less ASB. Post‐hoc analyses in these data revealed that these associations differed markedly from those with harsh parenting that suggested environmental influences on youth ASB.ConclusionsThese results strongly argue against a causal influence of low parental nurturance on youth ASB, and instead suggest that genetic influences and shared environmental confounds underlie their association. Further, findings strongly suggest that different parenting behaviors are associated with child ASB via different etiologic mechanisms.

A Baseline Model of PTSD From the ACES Cohort.

Post-traumatic stress disorder (PTSD) is a primary military psychiatric condition with complex etiology including strong genetic and/or environmental influences. Environmental influences and demographics can play a role in supporting underlying genetic traits for clinical utility evaluation as risk modifying factors. We are undertaking an IRB approved study to evaluate polygenic scores of PTSD risk in the adverse childhood experience and serotonin (ACES) transporter cohort. Baseline demographic characteristics and statistical modeling of 291 active duty service members from ACES cohort were used and excluded individuals with traumatic brain injury-induced loss of consciousness, pre-deployment PTSD or anxiety disorder, and pre-deployment prescription of antidepressants or psychoactive medications. Summary of categorical and numerical variables were evaluated using chi-square and t-test, respectively. We model PTSD risk and associated scores using linear and logistic regressions. The ACES subset was 79.1% males, multi-ancestry, and mean age of 38.3 years. Most PTSD individuals received behavioral therapy (89.6%) and/or prescribed antidepressants (67%) had higher scores in ACES, combat exposure scales, PTSD checklist military version, neurobehavioral symptom inventory, Pittsburg sleep quality index, insomnia severity index, and composite autonomic symptom score surveys and were less likely to expect future deployment. A positive correlation between age, total months deployed, ACES, CES, PCL-M, and positive-PTSD diagnosis were consistent but not in older individuals, who were more likely and frequently deployed although increasing risk for combat exposure. Demographic characteristics of the ACES cohort fit a coherent model of risk for PTSD to evaluate polygenic scores. Additional research is merited to understand PTSD effects on these confounding factors.

Supplemental Material for Development of Temperament Types From Infancy to Adolescence: Genetic and Environmental Influences With an Economically and Racially/Ethnically Diverse Sample

Supplemental Material for Development of Temperament Types From Infancy to Adolescence: Genetic and Environmental Influences With an Economically and Racially/Ethnically Diverse Sample

The genetic and environmental etiology of novel frequency-driven regional parcellations of abnormal white matter.

The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our data-driven regional parcellation approach, we created a probability distribution atlas using Vietnam Era Twin Study of Aging (VETSA) data (n = 475, mean age 67.6 years) and applied a watershed algorithm to define separate regional parcellations. We report biometrical twin modeling for five anatomically distinct regions: (1) Posterior, (2) Superior frontal and parietal, (3) Anterior and inferior frontal with deep areas, (4) Occipital, and (5) Anterior periventricular. We tested competing multivariate hypotheses to identify unique influences and to explain sources of covariance among the parcellations. Family aggregation could be entirely explained by additive genetic influences, with additive genetic variance (heritability) ranging from 0.69 to 0.79. Most genetic correlations between parcellations ranged from moderate to high (rg = 0.57-0.85), although two were small (rg = 0.35-0.39), consistent with varying degrees of unique genetic influences. This proof-of-principle investigation demonstrated the value of our novel, data-driven parcellations, with identifiable genetic and environmental differences, for future exploration.

Association between serotonin transporter gene polymorphism and obsessive–compulsive disorder in the Egyptian population

BackgroundObsessive–compulsive disorder (OCD) is a debilitating disorder that has multifactorial etiology including genetic, neurobiological, cognitive, and environmental influences. Genetic studies have focused on the genes of the serotonin system. This study aimed to look for the possible relation between the polymorphism in the promotor region of the serotonin transporter gene and obsessive–compulsive disorder in the Egyptian population.ResultsThis study included 94 OCD patients and 116 healthy control individuals. Blood samples were collected from all participants for DNA extraction and genotyping. The assessment of patients was done by application of the structured clinical interview according to DSM-V, the dimensional Yale-Brown Obsessive–Compulsive Scale. There was an association between serotonin transporter gene polymorphism and OCD development. The carriage of the short allele was a risk factor for having OCD.ConclusionObsessive–compulsive disorder is associated with serotonin transporter gene polymorphism. This will contribute to considering the genetic information of patients for the prediction of best drug response and tolerability by personalizing the choice of treatment.

A comparative study on lipid profile parameters in athlete and non-athlete adult males

Regular physical exercise has a major impact on lipid status. The particular characteristics of athletes' blood lipid profiles were examined in this literature study. When compared to a sex- and age-matched inactive group, professional athletes' blood lipid level was shown to be much better. Athletes perform lower levels of TC, LDL-C, and TG and equivalent or higher blood levels of HDL-C regardless of whether they participate in endurance or power sports. It was introduced that there are disparities in blood lipid levels and sports disciplines. Although there are many more elements that should be considered for future research, such as food, area of origin, exercise regimen, and even genetic susceptibility. To compare the lipid profile among athlete and no-athlete adult males. Case control study with sample size 150. Adult males of age group 20-50 &amp; apparently healthy males were taken. Serum lipid profile and various anthropometric measurements were done. Data Collection was done using a predesigned and pre-validated interview questionnaire. Serum cholesterol, Triglyceride, VLDL &amp; LDL values were raised in non-athletes compared to athletes and the difference was statistically significant. The serum HDL values were lower in non-athletes compared to the athletes and the difference was statistically significant (p&amp;#60;0.001). Our study concludes that athletes and non-athletes differ in their lipid profile status. Athletes have better lipid status as compared to non-athletes, thus well protected from the risk of cardiovascular diseases. Physical activity significantly promotes better lipid profile, irrespective of genetic influence.

Modeling embryo survival: Genetic and environmental influences on eye-up rate in a north American Atlantic salmon selective breeding program

Selective breeding programs improve target traits but can also unintentionally change genetically correlated traits in the selected strain. The U.S. Department of Agriculture–Agricultural Research Service National Cold Water Marine Aquaculture Center (NCWMAC) in Franklin, Maine maintains a North American Atlantic salmon selective breeding program focused on improving commercially important traits (e.g., carcass weight). However, the program has experienced a significant decline in the percent of eyed embryos over its 14 years of operation, leading to concerns that reproductive performance was being unintentionally changed by selection for the target traits. The aims of this study were to 1) model eye up success as a potentially heritable trait utilizing the recorded pedigree and 2) assess the relationship between eye-up rate and environmental conditions experienced by the broodstock. Over 14 years of data encompassing 1537 full-sib families produced by 1537 dams and 885 sires was analyzed. Counts of eyed embryos and carcass weight were analyzed with a linear multi-trait trait model that included maternal genetic effects and a spawn year effect to determine the strength of genetic and environmental influences on the eyed embryo rate. To investigate the environmental influences in more detail, we assessed the correlation between water quality parameters in the broodstock rearing system observed over the same 14-year time period and the estimated spawn year effects. There was small heritability of the direct genetic effect (0.059 ± 0.009) and the maternal genetic effect (0.039 ± 0.013). Comparatively, the proportion of phenotypic variance explained by the maternal environmental effect was moderate (0.165 ± 0.012). The genetic correlations between carcass weight and eye up rate were very small and had a large amount of uncertainty. The correlation between the direct genetic effects on eye-up and carcass weight was −0.0528 ± 0.1469 while the correlation between the maternal genetic effect on eye-up and the direct genetic effect on carcass weight was 0.2030 ± 0.1791. The correlation between maternal common environmental effects on the two traits was also low at 0.0676 ± −0.0804. The effect of spawn year was statistically significant (p < 0.01), and the values were negatively correlated with mean un-ionized ammonia (mg/L, −0.56, p = 0.04,), nitrate concentrations (mg/L r = −0.65, p = 0.01) and temperature (°C, r = −0.61, p = 0.02) experienced by the broodstock prior to spawning. Overall, the results suggest that the decrease in eyed embryos over time was not caused by inadvertent selection but instead due to increases in water temperature and/or nitrogenous waste concentrations in the broodstock rearing system. Further investigation of the mechanisms behind these apparent environmentally induced declines and potential mitigation measures to prevent decreases in eye-up rates are needed.

Mapping associations of polygenic scores with autistic and ADHD traits in a single city region.

The genetic and environmental aetiology of autistic and Attention Deficit Hyperactivity Disorder (ADHD) traits is known to vary spatially, but does this translate into variation in the association of specific common genetic variants? We mapped associations between polygenic scores for autism and ADHD and their respective traits in the Avon Longitudinal Study of Parents and Children (N = 4,255-6,165) across the area surrounding Bristol, UK, and compared them to maps of environments associated with the prevalence of autism and ADHD. Our results suggest genetic associations vary spatially, with consistent patterns for autistic traits across polygenic scores constructed at different p-value thresholds. Patterns for ADHD traits were more variable across thresholds. We found that the spatial distributions often correlated with known environmental influences. These findings shed light on the factors that contribute to the complex interplay between the environment and genetic influences in autistic and ADHD traits.

Applying an ELSI lens to real-world data and novel genomic insights for personalized mental healthcare.

Improving the understanding of the complex relationship between genetic predispositions, environmental influences, and sociocultural factors in the development and progression of mental illness is crucial for optimizing treatment efficacy and addressing longstanding health disparities. This paper discusses the ethical, legal, and social implications (ELSI) of recent advancements in biomedical research, particularly in genome-wide association studies (GWAS), phenome-wide association studies (PheWAS), and genome-wide environment interaction studies (GWEIS). Despite recent scientific progresses, challenges such as inadequate study methodology (e.g., correlational studies) and lack of diversity within study samples persist. Recent discoveries of several genetic variants of diseases, could augment and improve, or even challenge, existing understanding of the onset and management of mental illness. Leveraging real-world data (RWD), including electronic health record data (EHRs) focused on social determinant of health alongside biobank data, offers further opportunities to enhance the understanding of gene-environment interactions and inform efforts for reducing disparities in mental healthcare. Increased knowledge can support timely, holistic, evidence-based, and personalized care. Addressing ELSI considerations and maximizing the use of RWD is essential for advancing ethical and inclusive psychiatric genetics research, ultimately improving patient outcomes and promoting equitable access to evidence-based treatments.

Unraveling the Genetic Susceptibility of Irritable Bowel Syndrome: integrative genome-wide analyses in 845,492 individuals: a diagnostic study.

Irritable bowel syndrome (IBS) significantly impacts individuals due to its prevalence and negative effect on quality of life. Current genome-wide association studies (GWAS) have only identified a small number of crucial single nucleotide polymorphisms (SNPs), not fully elucidating IBS's pathogenesis. To identify genomic loci at which common genetic variation influence IBS susceptibility. Combining independent cohorts that in total comprise 65,840 cases of IBS and 788,652 controls, we performed a meta-analysis of genome-wide association studies (GWAS) of IBS. We also carried out gene mapping and pathway enrichment to gain insights into the underlying genes and pathways through which the associated loci contribute to disease susceptibility. Furthermore, we performed transcriptome analysis to deepen our understanding. IBS risk models were developed by combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. We detect the phenotype association for IBS utilizing PRS-based phenome-wide association (PheWAS) analyses, linkage disequilibrium score regression, and Mendelian randomization. The GWAS meta-analysis identified 10 IBS risk loci, seven of which were novel (rs12755507, rs34209273, rs34365748, rs67427799, rs2587363, rs13321176, rs1546559). Multiple methods identified nine promising IBS candidate gene (PRRC2A, COP1, CADM2, LRP1B, SUGT1, MED12L, P2RY14, PHF2, SHISA6) at 10 GWAS loci. Transcriptome validation also revealed differential expression of these genes. Phenome-wide associations between PRS-IBS and nine traits (neuroticism, diaphragmatic hernia, asthma, diverticulosis, cholelithiasis, depression, insomnia, COPD, and BMI) were identified. The six diseases (asthma, diaphragmatic hernia, diverticulosis, insomnia major depressive disorder and neuroticism) were found to show genetic association with IBS and only major depressive disorder and neuroticism were found to show causality with IBS. We identified seven novel risk loci for IBS and highlight the substantial influence on genetic risk harboured. Our findings offer novel insights into aetiology and phenotypic association of IBS and lay the foundation for therapeutic targets and interventional strategies.

Genome-wide study identifies novel genes associated with bone toxicities in children with acute lymphoblastic leukaemia.

Bone toxicities are common among paediatric patients treated for acute lymphoblastic leukaemia (ALL) with potentially major negative impact on patients' quality of life. To identify the underlying genetic contributors, we conducted a genome-wide association study (GWAS) and a transcriptome-wide association study (TWAS) in 260 patients of European-descent from the DFCI 05-001 ALL trial, with validation in 101 patients of European-descent from the DFCI 11-001 ALL trial. We identified a significant association between rs844882 on chromosome 20 and bone toxicities in the DFCI 05-001 trial (p = 1.7 × 10-8). In DFCI 11-001 trial, we observed a consistent trend of this variant with fracture. The variant was an eQTL for two nearby genes, CD93 and THBD. In TWAS, genetically predicted ACAD9 expression was associated with an increased risk of bone toxicities, which was confirmed by meta-analysis of the two cohorts (meta-p = 2.4 × 10-6). In addition, a polygenic risk score of heel quantitative ultrasound speed of sound was associated with fracture risk in both cohorts (meta-p = 2.3 × 10-3). Our findings highlight the genetic influence on treatment-related bone toxicities in this patient population. The genes we identified in our study provide new biological insights into the development of bone adverse events related to ALL treatment.

Exploring the Genetic Heterogeneity of Alzheimer's Disease: Evidence for Genetic Subtypes.

Alzheimer's disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins. We investigated genetic heterogeneity in AD risk through a multi-step analysis. We performed principal component analysis (PCA) on AD-associated variants in the UK Biobank (AD cases = 2,739, controls = 5,478) to assess structured genetic heterogeneity. Subsequently, a biclustering algorithm searched for distinct disease-specific genetic signatures among subsets of cases. Replication tests were conducted using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (AD cases = 500, controls = 470). We categorized a separate set of ADNI individuals with mild cognitive impairment (MCI; n = 399) into genetic subtypes and examined cognitive, amyloid, and tau trajectories. PCA revealed three distinct clusters ("constellations") driven primarily by different correlation patterns in a region of strong LD surrounding the MAPT locus. Constellations contained a mixture of cases and controls, reflecting disease-relevant but not disease-specific structure. We found two disease-specific biclusters among AD cases. Pathway analysis linked bicluster-associated variants to neuron morphogenesis and outgrowth. Disease-relevant and disease-specific structure replicated in ADNI, and bicluster 2 exhibited increased cerebrospinal fluid p-tau and cognitive decline over time. This study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time.

Genetic effects on the skin methylome in healthy older twins

Whole-skin DNA methylation variation has been implicated in several diseases, including melanoma, but its genetic basis has not yet been fully characterized. Using bulk skin tissue samples from 414 healthy female UK twins, we performed twin-based heritability and methylation quantitative trait loci (meQTL) analyses for >400,000 DNA methylation sites. We find that the human skin DNA methylome is on average less heritable than previously estimated in blood and other tissues (mean heritability: 10.02%). meQTL analysis identified local genetic effects influencing DNA methylation at 18.8% (76,442) of tested CpG sites, as well as 1,775 CpG sites associated with at least one distal genetic variant. As a functional follow-up, we performed skin expression QTL (eQTL) analyses in a partially overlapping sample of 604 female twins. Colocalization analysis identified over 3,500 shared genetic effects affecting thousands of CpG sites (10,067) and genes (4,475). Mediation analysis of putative colocalized gene-CpG pairs identified 114 genes with evidence for eQTL effects being mediated by DNA methylation in skin, including in genes implicating skin disease such as ALOX12 and CSPG4. We further explored the relevance of skin meQTLs to skin disease and found that skin meQTLs and CpGs under genetic influence were enriched for multiple skin-related genome-wide and epigenome-wide association signals, including for melanoma and psoriasis. Our findings give insights into the regulatory landscape of epigenomic variation in skin.

Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia.

Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. Our goal was to investigate the effects of genetic variants on risk and time to LID. We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147). This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genetic Influences of Proinflammatory Cytokines on Pain Severity in Patients with Temporomandibular Disorders.

This case-control study investigated single nucleotide polymorphism (SNP) genotypes (CXC motif chemokine ligand 8 (CXCL8): rs2227306 and rs2227307 and tumor necrosis factor (TNF): rs1800629) in 85 patients with pain-related temporomandibular disorders (TMDp) and 85 controls to explore their associations with TMDp presence, pain intensity (low/high), and the presence of chronic arthralgia/myalgia. TMDp was diagnosed using a validated protocol, and polymorphisms were genotyped from buccal mucosa swabs using TaqMan assays. High pain intensity individuals had an increased risk for carrying minor allele "G" (rs2227307) and "T" (rs2227306) compared to controls (76% vs. 55.3%, p = 0.012; 72% vs. 54.1%, p = 0.030, respectively). Carriers of the minor allele "G" (rs2227307) were more prevalent in TMDp patients with arthralgia compared to controls (70.30% vs. 55.30%, p = 0.037). According to logistic regression, the most important predictors for high pain intensity were minor allele "G" of rs2227307 (OR 2.435, 95% CI 1.123-5.282), increasing age (OR 1.038, 95% CI 1.002-1.075), and female sex (OR 4.592, 95% CI 1.289-16.361). The explored gene polymorphisms were not significant risk factors for TMDp presence. These findings highlight the importance of genetic variations, particularly rs2227307, in understanding the diverse clinical manifestations of temporomandibular disorders.