European Populations Research Articles

Candidate SNPs associated with anxiety and depression in children and adolescents in the USH1C gene

Introduction: Anxiety and depression in children and adolescents are growing concerns globally, with significant rates of diagnosis across diverse populations. According to the Centers for Disease Control and Prevention (CDC), approximately 7.1% of children aged 3 to 17 years in the United States have been diagnosed with anxiety, and 3.2% with depression. The aim of this study is to analyze the correlation between SNPs in the USH1C gene and predisposition to anxiety and depression in children and adolescents from specific populations.Methods: Genotypes from the 1000 Genomes Project were used to evaluate SNPs in Southeast Asian and European populations. Linkage disequilibrium (LD) analysis was performed using VcfTools and the biological effects of the SNPs were assessed using the Variant Effect Predictor (VEP).Results: Two SNPs, rs4757538 and rs16934376, were identified, which showed strong LD with SNP rs79878474 in South Asian populations (r² > 0.7), suggesting their possible association with anxiety and depression. Allele frequencies varied significantly between populations. Hardy-Weinberg equilibrium analysis showed significant imbalance at the global level, but not within individual populationsConclusions: The analyzed SNPs might be related to predisposition to anxiety and depression in specific populations. These findings underline the importance of considering genetic diversity in future studies and developing personalized interventions to address these disorders in children and adolescents

Intervertebral disc degenerative disease in South Africa: a case-control analysis of selected gene variants

BackgroundIntervertebral disc (IVD) degenerative disease is a multifactorial disease for which genetics plays an integral role. Several genes, and their variants, associated with the development and progression of IVD degenerative disease have been identified. While several studies have investigated these genes in Asian and European populations, no available evidence exists for the South African population. Therefore, this study aimed to investigate these parameters.Methods and resultsBiological samples were collected in the form of buccal swabs from patients and DNA was extracted using a standard salt-lysis protocol. DNA purity and quantity was assessed by spectrophotometry, and subsequent genotyping was performed using the MassARRAY®System IPLEX extension reaction. For associations between variants and the presence of IVD degenerative disease, odds ratios (OR), confidence intervals (CI), chi-squared analysis and logistic regression was calculated. Age and sex were adjusted for, and Bonferroni’s correction was applied. This study found statistically significant associations for five of the evaluated single nucleotide polymorphisms (SNPs) with IVD degenerative disease, whereby IL-1α rs1304037 and rs1800587, ADAMTs-5 rs162509, and MMP-3 rs632478 demonstrated increased odds of a positive diagnosis for IVD degenerative disease, while decreased odds of IVD degenerative disease were seen for GDF-5 rs143383.ConclusionTo the best of our knowledge, this study represents the first of its kind to investigate the association of gene variants associated with IVD degenerative disease within the South African population. This study has shown that 5 of these gene variants were significantly associated with the presence of IVD degenerative disease, reflecting their integral roles in development and possible progression of the disease.

A comprehensive atlas of nuclear sequences of mitochondrial origin (NUMT) inserted into the pig genome

BackgroundThe integration of nuclear mitochondrial DNA (mtDNA) into the mammalian genomes is an ongoing, yet rare evolutionary process that produces nuclear sequences of mitochondrial origin (NUMT). In this study, we identified and analysed NUMT inserted into the pig (Sus scrofa) genome and in the genomes of a few other Suinae species. First, we constructed a comparative distribution map of NUMT in the Sscrofa11.1 reference genome and in 22 other assembled S. scrofa genomes (from Asian and European pig breeds and populations), as well as the assembled genomes of the Visayan warty pig (Sus cebifrons) and warthog (Phacochoerus africanus). We then analysed a total of 485 whole genome sequencing datasets, from different breeds, populations, or Sus species, to discover polymorphic NUMT (inserted/deleted in the pig genome). The insertion age was inferred based on the presence or absence of orthologous NUMT in the genomes of different species, taking into account their evolutionary divergence. Additionally, the age of the NUMT was calculated based on sequence degradation compared to the authentic mtDNA sequence. We also validated a selected set of representative NUMT via PCR amplification.ResultsWe have constructed an atlas of 418 NUMT regions, 70 of which were not present in any assembled genomes. We identified ancient NUMT regions (older than 55 million years ago, Mya) and NUMT that appeared at different time points along the Suinae evolutionary lineage. We identified very recent polymorphic NUMT (private to S. scrofa, with < 1 Mya), and more ancient polymorphic NUMT (3.5–10 Mya) present in various Sus species. These latest polymorphic NUMT regions, which segregate in European and Asian pig breeds and populations, are likely the results of interspecies admixture within the Sus genus.ConclusionsThis study provided a first comprehensive analysis of NUMT present in the Sus scrofa genome, comparing them to NUMT found in other species within the order Cetartiodactyla. The NUMT-based evolutionary window that we reconstructed from NUMT integration ages could be useful to better understand the micro-evolutionary events that shaped the modern pig genome and enriched the genetic diversity of this species.

Relationship between type 1 diabetes and autoimmune diseases in european populations: A two-sample Mendelian randomization study.

Previous studies have suggested an association between Type 1 diabetes (T1D) and autoimmune diseases (AIDs), but the causal relationship remains unclear. Therefore, this study utilizes publicly available Genome-Wide Association Studies (GWAS) databases and employs a two-sample Mendelian Randomization (MR) approach to explore the causal relationships between T1D and systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). Summary GWAS data for T1D, SLE, RA, and IBD were downloaded from open GWAS databases and the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). We employed a series of methods to select instrumental variables closely related to T1D. To enhance the reliability of our conclusions, we applied multiple robust analytical methods, with the inverse variance weighted (IVW) method as the primary approach. Validation and meta-analysis were conducted using the FinnGen consortium. Additionally, we assessed heterogeneity, pleiotropy, and sensitivity to ensure the robustness of our conclusions. A potential causal association was found between T1D and SLE (OR = 1.37, 95% CI = 1.26 - 1.49, P < 0.001), which was further confirmed by meta-analysis. Similarly, a potential causal association was found between T1D and RA (OR = 1.32, 95% CI = 1.17 - 1.50, P < 0.001), and this was also confirmed by meta-analysis. Although the association between T1D and IBD showed P < 0.05, the leave-one-out test did not pass, and further meta-analysis indicated no significant statistical association between them. Our study reveals the relationships between T1D and three clinically common autoimmune diseases (SLE, RA, and IBD). This research supplements previous studies and provides a reference for future clinical work.

Modifiable factors mediating the effects of educational attainment on gestational diabetes mellitus: A two-step Mendelian randomization study.

Although there is currently a wealth of evidence to indicate that maternal educational attainment is associated with gestational diabetes mellitus (GDM), the specific modifiable risk factors that mediate the causal relationship between these two variables have yet to be identified. To identify the specific modifiable risk factors that mediate the causal relationship between the level of maternal education and GDM. Mendelian randomization (MR) was conducted using data from genome-wide association studies of European populations. We initially performed a two-sample MR analysis using data on genetic variants associated with the duration of education as instruments, and subsequently adopted a two-step MR approach using metabolic and lifestyle factors as mediators to examine the mechanisms underlying the relationship between the level of maternal education and risk of developing GDM. In addition, we calculated the proportions of total causal effects mediated by identified metabolic and lifestyle factors. A genetically predicted higher educational attainment was found to be associated with a lower risk of developing GDM (OR: 0.71, 95%CI: 0.60-0.84). Among the metabolic factors assessed, four emerged as potential mediators of the education-GDM association, which, ranked by mediated proportions, were as follows: Waist-to-hip-ratio (31.56%, 95%CI: 12.38%-50.70%), body mass index (19.20%, 95%CI: 12.03%-26.42%), high-density lipoprotein cholesterol (12.81%, 95%CI: 8.65%-17.05%), and apolipoprotein A-1 (7.70%, 95%CI: 4.32%-11.05%). These findings proved to be robust to sensitivity analyses. Our findings indicate a causal relationship between lower levels of maternal education and the risk of developing GDM can be partly explained by adverse metabolic profiles.

Introgressive hybridisation puts the distinctive population of Apis mellifera mellifera in Ireland at risk: evidence from a multidisciplinary approach

Apis mellifera mellifera a honey bee subspecies at risk of extinction across much of its range has a stronghold in Ireland where it is the native honey bee subspecies and is referred to as the black bee. However, an increase in imports of other subspecies and commercial strains is now a major threat to its genetic integrity. Furthermore, despite assertions by Irelands’ beekeepers that the black bee is a distinct ecotype, little taxonomic work has focused on this population. Here we liaise with beekeepers and assess the managed honey bee cohort for signs of increased introgression. We also investigate morphological variation in A. m. mellifera colonies to establish for the first time a description of this subspecies in Ireland. SNPs and mitochondrial data indicate a further increase in introgression in the population even though much of the population remains A. m. mellifera. The morphology of Irish A. m. mellifera has deviated significantly from European populations and can be characterised as being smaller and hairier, with a broad abdomen, shorter legs and a shorter proboscis. Their fore wings are longer but with a smaller cubital index. These attributes may have evolved as adaptations to the unique environmental and climatic conditions found in Ireland but may also have been influenced by artificial selection and/or genetic drift.

Sleep duration and heart failure risk: Insights from a Mendelian Randomization Study.

To investigate the causal relationship between sleep duration and heart failure (HF) in a European population. We focused on the continuous sleep duration of 460,099 European individuals as our primary exposure. Genome-wide significant single nucleotide polymorphisms (SNPs, n = 9851,867) linked to continuous sleep duration were adopted as instrumental variables. The outcome of interest was based on HF events in a European cohort (n = 977,323; with 930,014 controls and 47,309 cases). We employed a two-sample Mendelian randomization (MR) approach to infer causality between sleep duration and the incidence of HF. For validation purposes, an additional cohort of 336,965 European individuals diagnosed with insomnia was selected as a secondary exposure group. Using its SNPs, a subsequent two-sample MR analysis was conducted with the HF cohort to further corroborate our initial findings. Employing the MR methodology, we selected 57 SNPs that are associated with sleep duration, and 24 SNPs that are associated with insomnia as instrumental variables. We discerned a substantial association between genetically inferred sleep duration and HF risk (odds ratio: 0.61; 95% confidence interval: 0.47-0.78, P < .0001). Our subsequent analysis highlighted a pronounced increased HF risk associated with insomnia (odds ratio: 1.54; 95% confidence interval: 1.08-2.17, P < .02). These conclusions were further bolstered by consistent results from sensitivity analyses. Our study suggests a causal linkage between sleep duration and the onset risk of HF in the European population. Notably, shorter sleep durations were associated with a heightened risk of HF.

Causal influence of plasma metabolites on age-related macular degeneration: A Mendelian randomization study.

Using genome-wide association study data from European populations, this research clarifies the causal relationship between plasma metabolites and age-related macular degeneration (AMD) and employs Metabo Analyst 5.0 for enrichment analysis to investigate their metabolic pathways. Employing Mendelian randomization analysis, this study leveraged single nucleotide polymorphisms significantly associated with plasma metabolites as instrumental variables. This approach established a causal link between metabolites and AMD. Analytical methods such as inverse-variance weighted, Mendelian randomization-Egger, and weighted median were applied to validate causality. Mendelian Randomization Pleiotropy Residual Sum and Outlier was utilized for outlier detection and correction, and Cochran's Q test was conducted to assess heterogeneity. To delve deeper into the metabolic characteristics of AMD, metabolic enrichment analysis was performed using Metabo Analyst 5.0. These combined methods provided a robust framework for elucidating the metabolic underpinnings of AMD. The 2-sample MR analysis, after meticulous screening, identified causal relationships between 88 metabolites and AMD. Of these, 16 metabolites showed a significant causal association. Following false discovery rate correction, 3 metabolites remained significantly associated, with androstenediol (3 beta, 17 beta) disulfate (2) exhibiting the most potent protective effect against AMD. Further exploration using Metabo Analyst 5.0 highlighted 4 metabolic pathways potentially implicated in AMD pathogenesis. This pioneering MR study has unraveled the causal connections between plasma metabolites and AMD. It identified several metabolites with a causal impact on AMD, with 3 maintaining significance after FDR correction. These insights offer robust causal evidence for future clinical applications and underscore the potential of these metabolites as clinical biomarkers in AMD screening, treatment, and prevention strategies.

Causality between neuroticism personality clusters and female reproductive diseases in European population: a two-sample bidirectional mendelian randomization study

BackgroundThe causality between neuroticism, a personality trait characterized by the tendency to experience negative emotions, and female reproductive diseases remains unclear. To provide evidence for the development of effective screening and prevention strategies, this study employed Mendelian randomization (MR) to investigate the causality between neuroticism clusters and female reproductive diseases.MethodsInstrumental variables were obtained from large-scale genome-wide association studies of populations of European descent involving three neuroticism clusters (depressed affect, worry, sensitivity to environmental stress, and adversity [SESA]) in the Complex Trait Genetics database and six female reproductive diseases (infertility, polycystic ovary syndrome [PCOS], spontaneous abortion, recurrent spontaneous abortion, endometriosis, and uterine fibroids) in the FinnGen database. The bidirectional two-sample MR analysis was conducted using the inverse variance-weighted, weighted median, and MR-Egger methods, whereas the sensitivity analysis was conducted using the Cochran’s Q-test, MR-Egger intercept, and leave-one-out analysis.ResultsIn the forward analysis, genetically predicted depressed affect and worry components of neuroticism significantly increased the risk of infertility (depressed affect: odds ratio [OR] = 1.399, 95% confidence interval [CI]: 1.054–1.856, p = 0.020; worry: OR = 1.587, 95% CI: 1.229–2.049, p = 0.000) and endometriosis (depressed affect: OR = 1.611, 95% CI: 1.234–2.102, p = 0.000; worry: OR = 1.812, 95% CI: 1.405–2.338, p = 0.000). Genetically predicted SESA component of neuroticism increased only the risk of endometriosis (OR = 1.524, 95% CI: 1.104–2.103, p = 0.010). In the reverse analysis, genetically predicted PCOS was causally associated with an increased risk of the worry component of neuroticism (Beta = 0.009, 95% CI: 0.003–0.016, p = 0.003).ConclusionsThe MR study showed that the three neuroticism personality clusters had definite causal effects on at least one specific female reproductive disease. Moreover, PCOS may increase the risk of the worry component of neuroticism. This finding suggests the need to screen for specific female reproductive diseases in populations with high neuroticism and assess the psychological status of patients with PCOS.

Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).

Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late-onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4-aminopyridine in a cohort of 102 patients bearing GAA repeat expansions. We compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post-mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B. In our cohort of 102 patients with SCA27B, we found that SCA27B was a late-onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post-mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4-aminopyridine. Our study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024.

A - 77 A Systematic Review of Current Diversity Representation in Neuropsychological Research

Abstract Objective This study investigated current representation of diverse samples in research published in four leading neuropsychology journals. Methods We reviewed 367 articles published in 2023 from Archives of Clinical Neuropsychology, Neuropsychology, Journal of the International Neuropsychological Society, and The Clinical Neuropsychologist. 34 review articles and 4 editorial/announcements were excluded leaving 321 articles coded for age, education, gender/sex, race/ethnicity, and sample country. Results Overall, 89.41% of studies reported gender/sex and 50.46% reported race/ethnicity. Out of 63 original articles that included European populations (e.g., France, Sweden, Denmark, etc.), 93.65% reported gender/sex and 12.7% reported race/ethnicity. Out of 172 original articles that included United States (U.S.) samples, 95.93% reported gender/sex and 80.23% reported race/ethnicity. Studies of U.S. samples reported the following average sociodemographic variables: education 14.94 years (SD = 3.72), age 50.32 years (SD = 21.39), gender/sex 48.09% female and 51.90% male, and race/ethnicity was 65.11% White, 6.64% Black/African American, 2.18% Asian, 1.06% American Indian/Alaskan Native, 0.43% Native Hawaiian/Pacific Islander, and 24.57% unknown/other/mixed race. Additionally, 9.82% of participants were Hispanic/Latino. Conclusions Roughly half of studies did not report on race/ethnicity and this was particularly notable for European samples with more homogeneous populations. Studies with U.S. samples had equitable gender/sex representation but participants were predominantly White and older middle aged. Inconsistencies in how studies stratified race/ethnicity resulted in a large percentage of individuals being classified as unknown/other/mixed. This review highlights the need for more diverse representation in neuropsychological research as Hispanic/Latino, Black/African American, and Asian groups were represented at half their actual numbers in the U.S. population (18.5%, 12.2%, and 5.9% respectively).

Developmental stage shapes the realized energy landscape for a flight specialist.

The heterogeneity of the physical environment determines the cost of transport for animals, shaping their energy landscape. Animals respond to this energy landscape by adjusting their distribution and movement to maximize gains and reduce costs. Much of our knowledge about energy landscape dynamics focuses on factors external to the animal, particularly the spatio-temporal variations of the environment. However, an animal's internal state can significantly impact its ability to perceive and utilize available energy, creating a distinction between the 'fundamental' and the 'realized' energy landscapes. Here, we show that the realized energy landscape varies along the ontogenetic axis. Locomotor and cognitive capabilities of individuals change over time, especially during the early life stages. We investigate the development of the realized energy landscape in the Central European Alpine population of the golden eagle Aquila chrysaetos, a large predator that requires negotiating the atmospheric environment to achieve energy-efficient soaring flight. We quantified weekly energy landscapes using environmental features for 55 juvenile golden eagles, demonstrating that energetic costs of traversing the landscape decreased with age. Consequently, the potentially flyable area within the Alpine region increased 2170-fold during their first three years of independence. Our work contributes to a predictive understanding of animal movement by presenting ontogeny as a mechanism shaping the realized energy landscape.

Diagnosis of sarcopenic obesity in Japan: Consensus statement of the Japanese Working Group on Sarcopenic Obesity.

Sarcopenic obesity is the co-existence of obesity and sarcopenia in individuals aged 40-75 years. The Japanese Working Group on Sarcopenic Obesity has developed diagnostic criteria tailored for the Japanese population, considering their unique characteristics compared with European populations. Our algorithm consists of two steps: screening and diagnosis. The screening of obesity mandates using waist circumference and/or body mass index (BMI) based on national standards, while screening for sarcopenia involves the "finger ring test" in addition to the Asian Working Group for Sarcopenia 2019 criteria. The final diagnosis of sarcopenia involves handgrip strength for low muscle strength, the five-times chair stand test for low physical function, and limb skeletal muscle mass (corrected for BMI) for low muscle mass. Obesity is assessed by visceral fat area or body fat percentage. Sarcopenic obesity is then categorized into Stage I, with muscle weakness/loss of function, loss of muscle mass, and obesity; or Stage II, which includes complications. Further clinical validation is needed to refine the consensus and age range. Geriatr Gerontol Int 2024; 24: 997-1000.

ZCCHC8 p.P410A disrupts nucleocytoplasmic localization, promoting idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease

BackgroundIdiopathic pulmonary fibrosis (IPF) is a special kind of chronic interstitial lung disease with insidious onset. Previous studies have revealed that mutations in ZCCHC8 may lead to IPF. The aim of this study is to explore the ZCCHC8 mutations in Chinese IPF patients.MethodsHere, we enrolled 124 patients with interstitial lung disease from 2017 to 2023 in our hospital. Whole exome sequencing and Sanger sequencing were employed to explore the genetic lesions of these patients.ResultsAmong these 124 patients, a novel mutation (NM_017612: c.1228 C > G/p.P410A) of Zinc Finger CCHC-Type Containing 8 (ZCCHC8)was identified in a family with IPF and chronic obstructive lung disease. As a component of the nuclear exosome-targeting complex that regulates the turnover of human telomerase RNA, ZCCHC8 mutations have been reported may lead to IPF in European population and American population. Functional study confirmed that the novel mutation can disrupt the nucleocytoplasmic localization of ZCCHC8, which further decreased the expression of DKC1 and RTEL1, and finally reduced the length of telomere and led to IPF and related disorders.ConclusionsWe may first report the ZCCHC8 mutation in Asian population with IPF. Our study broadens the mutation, phenotype, and population spectrum of ZCCHC8 deficiency.

Combining Historical and Molecular Data to Study Nearly Extinct Native Italian Grey Partridge (Perdix perdix) at the Turn of the Twentieth Century.

The grey partridge (Perdix perdix Linnaeus, 1758), is a polytypic species with seven recognized subspecies, including P. p. italica (Hartert, 1917), which is endemic to Italy. Until World War II, the species was widespread across Europe but severely declined due to anthropogenic causes, jeopardizing the Italian subspecies gene pool. Genetic characterization and haplotype identification were performed by analyzing the 5'-end of the mitochondrial control region (CR). A total of 15 haplotypes were detected, seven of which were present in the population before 1915. Among them, three haplotypes were never detected again in the individuals collected after 1915. Interestingly, eight of the 15 haplotypes detected in Italian museum samples belonged exclusively to individuals collected after 1915. The obtained data highlight a high presence of specimens originating from other European populations and, despite all the conservation efforts, suggest an uncertain situation of the subspecies in Italy. This research was strongly backed up by extensive bibliographic research on historical documents, allowing the identification of hundreds of restocking events all over Italy. This is an integral part of this research and has laid the foundations for identifying and circumscribing historical periods in which introductions from the rest of Europe had different pressures, aiming to define a baseline.

Exploring genetic associations between metabolites and atopic dermatitis: insights from bidirectional Mendelian randomization analysis in European population.

There is growing evidence indicating a complex interaction between blood metabolites and atopic dermatitis (AD). The objective of this study was to investigate and quantify the potential influence of plasma metabolites on AD through Mendelian randomization (MR) analysis. Our procedures followed these steps: instrument variable selection, primary analysis, replication analysis, Meta-analysis of results, reverse MR analysis, and multivariate MR (MVMR) analysis. In our study, the exposure factors were derived from the Canadian Longitudinal Study on Aging (CLSA), encompassing 8,299 individuals of European descent and identifying 1,091 plasma metabolites and 309 metabolite ratios. In primary analysis, AD data, was sourced from the GWAS catalog (Accession ID: GCST90244787), comprising 60,653 cases and 804,329 controls. For replication, AD data from the Finnish R10 database included 15,208 cases and 367,046 controls. We primarily utilized the inverse variance weighting method to assess the causal relationship between blood metabolites and AD. Our study identified significant causal relationships between nine genetically predicted blood metabolites and AD. Specifically, 1-palmitoyl-2-stearoyl-GPC (16:0/18:0) (OR = 0.92, 95% CI 0.89-0.94), 1-methylnicotinamide (OR = 0.93, 95% CI 0.89-0.98), linoleoyl-arachidonoyl-glycerol (18:2/20:4) [1] (OR = 0.94, 95% CI 0.92-0.96), and 1-arachidonoyl-GPC (20:4n6) (OR = 0.94, 95% CI 0.92-0.96) were associated with a reduced risk of AD. Conversely, phosphate / linoleoyl-arachidonoyl-glycerol (18:2/20:4) [2] (OR = 1.07, 95% CI 1.04-1.10), docosatrienoate (22:3n3) (OR = 1.07, 95% CI 1.04-1.10), retinol (Vitamin A) / linoleoyl-arachidonoyl-glycerol (18:2/20:4) [2] (OR = 1.08, 95% CI 1.05-1.11), retinol (Vitamin A) / linoleoyl-arachidonoylglycerol (18:2/20:4) [1] (OR = 1.08, 95% CI 1.05-1.12), and phosphate / linoleoyl-arachidonoyl-glycerol (18:2/20:4) [1] (OR = 1.09, 95% CI 1.07-1.12 were associated with an increased risk of AD. No evidence of reverse causality was found in the previously significant results. MVMR analysis further confirmed that 1-palmitoyl-2-stearoyl-GPC (16:0/18:0) and 1-methylnicotinamide are independent and dominant contributors to the development of AD. Our study revealed a causal relationship between genetically predicted blood metabolites and AD. This discovery offers specific targets for drug development in the treatment of AD patients and provides valuable insights for investigating the underlying mechanisms of AD in future research.

Genetic modifiers of body mass index in individuals with cystic fibrosis

To identify modifier loci underlying variation in body mass index (BMI) in persons with cystic fibrosis (pwCF), we performed a genome-wide association study (GWAS). Utilizing longitudinal height and weight data, along with demographic information and covariates from 4,393 pwCF, we calculated AvgBMIz representing the average of per-quarter BMI Z scores. The GWAS incorporated 9.8M single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF)>0.005 extracted from whole-genome sequencing (WGS) of each study subject. We observed genome-wide significant association with a variant in FTO (FaT mass and Obesity-associated gene; rs28567725; p value= 1.21e-08; MAF= 0.41, β= 0.106; n= 4,393 individuals) and a variant within ADAMTS5 (A Disintegrin And Metalloproteinase with ThromboSpondin motifs 5; rs162500; p value= 2.11e-10; MAF= 0.005, β= -0.768; n= 4,085 pancreatic-insufficient individuals). Notably, BMI-associated variants in ADAMTS5 occur on a haplotype that is much more common in African (AFR, MAF= 0.183) than European (EUR, MAF= 0.006) populations (1000 Genomes project). A polygenic risk score (PRS) calculated using 924 SNPs (excluding 17 in FTO) showed significant association with AvgBMIz (p value= 2.2e-16; r2= 0.03). Association between variants in FTO and the PRS correlation reveals similarities in the genetic architecture of BMI in CF and the general population. Inclusion of Black individuals in whom the single-gene disorder CF is much less common but genomic diversity is greater facilitated detection of association with variants that are in LD with functional SNPs in ADAMTS5. Our results illustrate the importance of population diversity, particularly when attempting to identify variants that manifest only under certain physiologic conditions.

Multi-trait and multi-ancestry genetic analysis of comorbid lung diseases and traits improves genetic discovery and polygenic risk prediction.

While respiratory diseases such as COPD and asthma share many risk factors, most studies investigate them in insolation and in predominantly European ancestry populations. Here, we conducted the most powerful multi-trait and -ancestry genetic analysis of respiratory diseases and auxiliary traits to date. Our approach improves the power of genetic discovery across traits and ancestries, identifying 44 novel loci associated with lung function in individuals of East Asian ancestry. Using these results, we developed PRSxtra (cross TRait and Ancestry), a multi-trait and -ancestry polygenic risk score approach that leverages shared components of heritable risk via pleiotropic effects. PRSxtra significantly improved the prediction of asthma, COPD, and lung cancer compared to trait- and ancestry-matched PRS in a multi-ancestry cohort from the All of Us Research Program, especially in diverse populations. PRSxtra identified individuals in the top decile with over four-fold odds of asthma and COPD compared to the first decile. Our results present a new framework for multi-trait and -ancestry studies of respiratory diseases to improve genetic discovery and polygenic prediction.

Dietary Inflammatory Index and Blood Pressure Levels in Mexican Adults.

The relationship between the dietary inflammatory index and blood pressure has been evaluated in European and American populations. This association remains unexplored in Mexico, where outcomes may differ due to the populace's ancestral heritage and its diverse dietary habits. We used the Health Workers Cohort Study (2004 to 2018). DII intake was assessed using a food frequency questionnaire. Blood pressure was measured following standardized procedures and techniques. Fixed-effects linear regression and Cox regression models were utilized as the statistical approaches. In the first approach, we observed a positive association between changes in DII intake and changes in both systolic (SBP β: 3.23, 95% CI 1.11, 5.34) and diastolic blood pressure (DBP β: 1.01, 95% CI -0.43, 2.44). When stratified by hypertension, these associations were magnified in participants with hypertension (SBP β: 6.26, 95% CI 2.63, 9.89; DBP β: 1.64, 95% CI -0.73, 4.02). In the second approach, interactions between sex and age categories were explored. Participants in the highest DII category were associated with an increased risk of hypertension, particularly among young women (HR: 3.16, 95% CI 1.19, 8.43). Results suggest that a pro-inflammatory diet is associated with an increase in blood pressure over time among Mexican population.

Causal links between immune cells and asthma: Insights from a Mendelian Randomization analysis

Objectives Recent studies suggest immunophenotypes may play a role in asthma, but their causal relationship has not been thoroughly examined. Methods We used single nucleotide polymorphism (SNP)-derived instrumental variables. Summary data from 731 immune cell profiles and asthma cases were analyzed from genome-wide association studies (GWAS) of European populations. Mendelian Randomization (MR) analyses included inverse variance weighted (IVW), weighted median, and MR–Egger methods. Pleiotropy was assessed using the MR-Egger intercept and MR pleiotropy residual sum and outlier (MR-PRESSO) tests. Reverse MR analysis explored bidirectional causation between asthma and immunophenotypes. All statistical analyses were conducted using R software. Results MR analysis identified 108 immune signatures potentially contributing to asthma. Two immunophenotypes were significantly associated with asthma risk: CD4+ secreting Treg cells in allergic asthma (ORIVW = 1.078; 95% CI: 1.036–1.122; PIVW = 0.0002) and IgD + CD38− %lymphocyte cells in non-allergic asthma (ORIVW = 1.123; 95% CI: 1.057–1.194; PIVW = 0.0002). Conclusions This study highlights the causal associations between specific immunophenotypes and asthma risk, providing new insights into asthma pathogenesis.