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Results for “Genetic causality”

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PubMed2026

Mapping the causal chain from genetic risk variants to lipid dysmetabolism in Parkinson's disease.

The molecular pathways linking genetic variants to Parkinson's disease (PD) onset and progression remain incompletely defined; however, risk alleles in multiple genes, including GBA1, strongly implicate lipid metabolism. To systematically identify causal biomarker signatures, we analysed comprehensive metabolome profiles from blood plasma in 149 PD patients and 150 controls, along with complementary genetic, RNA-sequencing and metabolic data from other available clinical and pathologic cohorts. Using colocalization and summary-data-based Mendelian randomization, we tested whether expression and metabolic quantitative trait loci mediate the association between implicated genetic variants and PD risk. We further integrated differential metabolomics and proteomics from blood and brain to reveal pertinent mechanisms. We show that common PD risk variants at the serine palmitoyltransferase small subunit B (SPTSSB) locus, a key regulator of de novo sphingolipid biosynthesis, are associated with increased SPTSSB brain expression and elevated plasma ceramides. Additional analyses strongly support our hypothesis that a common SPTSSB causal variant is responsible for PD risk as well as the expression and metabolic quantitative trait loci. Multiple sphingolipids and fatty acid derivatives were perturbed in PD, and we identified both unique and shared features with the Alzheimer's disease metabolome. A PD acylcarnitine signature was further replicated in human post-mortem brain tissue, when comparing those with or without preclinical Lewy body pathology. Integrated analysis of complementary brain proteomic profiles revealed dysregulation of mitochondrial processes dependent on acylcarnitines, including fatty acid beta-oxidation, the tricarboxylic acid cycle and oxidative phosphorylation. Our results identify promising biomarkers and reveal a causal chain linking genetic variation to altered gene/protein expression, lipid dysmetabolism, and the manifestation of PD.

Humans↗
PubMed2026

Genetic evidence for causality of late chronotype on metabolic syndrome in East Asians and Europeans.

CONTEXT: The impact of chronotype-defined as an individuals' inherent preference of sleep timing-and its genetic determinants on metabolic syndrome (MetS) has been less studied. OBJECTIVE: This study investigated the causal relationship between late chronotype and MetS using Mendelian randomization (MR) analysis, based on data from the Taiwan Biobank (TWB) and parallel analyses in the UK Biobank (UKB). METHODS: A total of 36,845 participants from TWB served as the discovery cohort, and 235,639 participants from UKB served as the replication cohort. Late chronotype was defined in TWB as a preference for bedtime after midnight, and in UKB as self-report as being an 'evening' person. The association between late chronotype and MetS, along with its components, was evaluated in TWB, and validated in UKB. Genome-wide association analyses for late chronotype were first conducted in TWB and then meta-analyzed with UKB. Polygenic risk scores (PRS) for late chronotype were constructed and tested for association with MetS. Causality between late chronotype and MetS was examined using one-sample MR analysis in TWB and validated in UKB. RESULTS: Late chronotype was significantly associated with MetS, as well as with central obesity, hyperglycemia, and hypertriglyceridemia, in both TWB and UKB (all P&#xa0;<&#xa0;0.0083, considering Bonferroni correction). The constructed PRS of late chronotype also showed significant associations with MetS and several of its components (several P&#xa0;<&#xa0;0.0083, considering Bonferroni correction). Findings from the one-sample MR analysis indicated a potential causal effect of late chronotype on MetS. CONCLUSIONS: This study provides evidence of a robust association between late chronotype and MetS across populations of diverse ancestry, including Taiwanese and European.

Humans↗
PubMed2026

Robust human genetic evidence supporting causal effects of FGF21 on reducing alcohol consuming behaviours.

BACKGROUND: Alcohol use disorder (AUD) represents a tremendous societal burden, yet few efficacious therapies are available and widely used. Pre-clinical and human observational data support fibroblast growth factor 21 (FGF21) as a promising therapeutic target for the treatment of AUD. The objective of this study is to identify a robust genetic instrument for FGF21 agonism and leverage it to explore the effects of FGF21 agonism on AUD and related traits, as well as metabolic outcomes more widely. METHODS: We first compared associations with the positive control outcomes of liver fat and liver cirrhosis risk for the FGF21 cis-protein quantitative trait locus (cis-pQTL) (rs838131) to those for the common allele FGF21 L174P missense variant (rs739320). Having identified the L174P missense variant as a plausible genetic instrument, we subsequently performed association analyses investigating effects on AUD, related traits, and metabolic outcomes more widely. Finally, we performed colocalisation analyses to test whether observed association results reflect a causal mechanism that overlaps with the clinical effects of FGF21 on liver fat and liver cirrhosis. RESULTS: Consistent association and colocalisation evidence support a protective association between genetically predicted FGF21 agonism and alcohol consumption (association p&#x2009;=&#x2009;1&#x2009;&#xd7;&#x2009;10-18, colocalisation posterior probability&#x2009;=&#x2009;0.90), problematic alcohol use (association p&#x2009;=&#x2009;0.02, posterior probability&#x2009;=&#x2009;0.64), and AUD (association p&#x2009;=&#x2009;9&#x2009;&#xd7;&#x2009;10-8, posterior probability&#x2009;=&#x2009;0.97). Similar evidence was also observed for favourable effects of FGF21 on improving kidney function, lowering triglyceride levels, lowering proportional energy intake from carbohydrates, increasing proportional energy intake from protein and fat, increasing body weight and lowering waist-to-hip ratio. CONCLUSIONS: This study identifies a genetic instrument for FGF21 effects to provide causal human evidence supporting favourable effects of FGF21 analogues for the treatment of AUD and related traits, as well as on metabolic outcomes more broadly. Further clinical study is duly warranted.

Humans↗
PubMed2024

Genetic evidence for causal association between migraine and dementia: a mendelian randomization study.

BACKGROUND: There is an association between migraine and dementia, however, their causal relationship remains unclear. This study employed bidirectional two-sample Mendelian randomization (MR) to investigate the potential causal relationship between migraine and dementia and its subtypes: Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). METHODS: Summary-level statistics data were obtained from publicly available genome-wide association studies (GWAS) for both migraine and five types of dementia. Single nucleotide polymorphisms (SNPs) associated with migraine and each dementia subtype were selected. MR analysis was conducted using inverse variance weighting (IVW) and weighted median (WM) methods. Sensitivity analyses included Cochran's Q test, MR pleiotropy residual sum and outlier (MR-PRESSO) analysis, the intercept of MR-Egger, and leave-one-out analysis. RESULTS: Migraine showed a significant causal relationship with AD and VaD, whereas no causal relationship was observed with all-cause dementia, FTD, or DLB. Migraine may be a potential risk factor for AD (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 0.02-0.14; P&#x2009;=&#x2009;0.007), while VaD may be a potential risk factor for migraine (OR: 1.04; 95% CI: 0.02-0.06; P&#x2009;=&#x2009;7.760E-5). Sensitivity analyses demonstrated the robustness of our findings. CONCLUSION: Our study suggest that migraine may have potential causal relationships with AD and VaD. Migraine may be a risk factor for AD, and VaD may be a risk factor for migraine. Our study contributes to unraveling the comprehensive genetic associations between migraine and various types of dementia, and our findings will enhance the academic understanding of the comorbidity between migraine and dementia.

Humans↗
PubMed2024

The causal relationship between genetically predicted blood metabolites and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Numerous metabolomic studies have confirmed the pivotal role of metabolic abnormalities in the development of idiopathic pulmonary fibrosis (IPF). Nevertheless, there is a lack of evidence on the causal relationship between circulating metabolites and the risk of IPF. METHODS: The potential causality between 486 blood metabolites and IPF was determined through a bidirectional two-sample Mendelian randomization (TSMR) analysis. A genome-wide association study (GWAS) involving 7,824 participants was performed to analyze metabolite data, and a GWAS meta-analysis involving 6,257 IPF cases and 947,616 control European subjects was conducted to analyze IPF data. The TSMR analysis was performed primarily with the inverse variance weighted model, supplemented by weighted mode, MR-Egger regression, and weighted median estimators. A battery of sensitivity analyses was performed, including horizontal pleiotropy assessment, heterogeneity test, Steiger test, and leave-one-out analysis. Furthermore, replication analysis and meta-analysis were conducted with another GWAS dataset of IPF containing 4,125 IPF cases and 20,464 control subjects. Mediation analyses were used to identify the mediating role of confounders in the effect of metabolites on IPF. RESULTS: There were four metabolites associated with the elevated risk of IPF, namely glucose (odds ratio [OR] = 2.49, 95% confidence interval [95%CI] = 1.13-5.49, P = 0.024), urea (OR = 6.24, 95% CI = 1.77-22.02, P = 0.004), guanosine (OR = 1.57, 95%CI = 1.07-2.30, P = 0.021), and ADpSGEGDFXAEGGGVR (OR = 1.70, 95%CI = 1.00-2.88, P = 0.0496). Of note, the effect of guanosine on IPF was found to be mediated by gastroesophageal reflux disease. Reverse Mendelian randomization analysis displayed that IPF might slightly elevate guanosine levels in the blood. CONCLUSION: Conclusively, hyperglycemia may confer a promoting effect on IPF, highlighting that attention should be paid to the relationship between diabetes and IPF, not solely to the diagnosis of diabetes. Additionally, urea, guanosine, and ADpSGEGDFXAEGGGVR also facilitate the development of IPF. This study may provide a reference for analyzing the potential mechanism of IPF and carry implications for the prevention and treatment of IPF.

Humans↗
PubMed1976

Test of the hypothesis that embryonic face shape is a causal factor in genetic predisposition to cleft lip in mice.

It was proposed that embryonic face shape is one of the quantitative variables underlying the threshold trait, cleft lip. To test the hypothesis several facial dimensions were measured in photographs of embryos at an early stage of formation of the face in 3 lines of mice. The lines had been selected from one original population using frequency of cleft lip induced by 6-aminonicotinamide as the selection criterion. Line L was susceptible to spontaneous cleft lip; lines M and C were not. Line L had a significantly smaller distance between the nasal pits than the other 2 lines, but did not differ in overall head size. A trend towards reduced angle between the medial nasal processes in the L line was noted, though this was not statistically significant. These results were predicted by the face-shape hypothesis.

Animals↗
PubMed1985

[Cerebral palsy--investigation of its causal factors and genetical background].

In the last 30 years the prevalence rate of cerebral palsy (CP) has remarkably decreased in Japan. The decrease is arbitrarily attributed to the reduced frequency of such risk factors for CP, as low birthweight, severe asphyxia, and kernicterus in the neonatal period. However, there is no statistical data providing the evidence that CP patients complicating these risk factors have actually decreased so far. In order to make clear the bases of the decrease in prevalence of CP, we examined the changing patterns in the suggested cause of CP, experienced in the last 30 years. The investigation included the maternal condition of pregnancy and delivery, in relation to the neonatal risk factors, and genetic background of the family. In CP, low birthweight babies of 2500 gm or less were common (36.9%) and the mean birthweight (2689 gm) was obviously smaller than that of general population. In spite of the constant decline of the incidence of low birthweight babies in the general population in the last 30 years, the ratio of low birthweight to total births in CP group had not changed in this study period. It was concluded that the low birthweight following premature birth is still an important predisposing factor of CP. Asphyxia was frequently seen in the CP population. The rate of asphyxia was significantly higher in the group with a normal birthweight more than 2501 gm (58.4%), or gestational weeks longer than 36 weeks (57.7%), comparing with that of low birthweight (41.1%), or premature (40.7%) group.(ABSTRACT TRUNCATED AT 250 WORDS)

Asphyxia Neonatorum↗
PubMed2026

Shared Genetic Basis, Biological Function and Causal Relationship Between Sleep Traits and Hypothyroidism: Evidence from a Comprehensive Genetic Analysis.

BACKGROUND: This research attempts to clarify whether there are any genetic similarities between sleep traits and hypothyroidism based on publicly accessible large-scale genomewide association studies. METHODS: The methodology included colocalization analysis, cross-phenotype association analysis, and linkage disequilibrium score regression analysis to find common genetic overlap. Through tissue function specificity and functional mapping, we were able to identify the shared genetic level. Genetic instrumental factors were used for causal inference in two-sample univariate and multivariable Mendelian randomization analyses. RESULTS: A hereditary correlation between hypothyroidism and napping during the day and getting up in the morning (rg= -0.0982, P= 0.0007; rg= -0.101, P= 0.0001). MAGI3, and HLA-DRB1 BX296568.1 may be potential targets for shared treatments. Colocalization and tissue-specific analysis demonstrated that the common genes and SNPs were identified in the thyroid, lung, brain, and lymphatic tissues. Functional analysis emphasized the importance of these common genes in processes like as protein transport, inflammatory response, and MHC class II protein synthesis. Furthermore, an association has been established between hypothyroidism and sleep duration (IVW, OR 1.5208; 95% CI 1.1142-2.0758, P=0.0082) and getting up in the morning (IVW, OR 1.8375; 95%CI: 1.4502-2.3284, P=4.73E-07). Furthermore, the reverse MR analysis revealed no causal connection between aberrant sleep traits and hypothyroidism. The enduring impact of insomnia on hypothyroidism persists despite controlling for alcohol consumption and smoking habits. CONCLUSION: Certain genetic correlations between sleep traits and hypothyroidism have been emphasized. These findings may elucidate the origin of comorbidity and have implications for future clinical trials.

Humans↗
PubMed2007

Anticipated uptake of genetic testing for familial melanoma in an Australian sample: An exploratory study.

INTRODUCTION: The potential role of genetic testing in families with an inherited pattern of melanoma is a complex issue, and yet limited data exist on perceptions of predictive genetic testing for mutations among individuals at high risk of melanoma. METHODOLOGY: Forty semi-structured interviews were undertaken with affected and unaffected individuals at either high or average risk of developing melanoma due to family history. Interviews addressed key issues such as: the role of genetics in causal attributions for melanoma; genetic testing intentions and motivations; perceived accuracy of genetic testing in predicting melanoma onset, and the impact of varied accuracy on testing intentions; views on the testing of children; perceived benefits and limitations of testing; and information needs and communication preferences. RESULTS: In-depth thematic analysis revealed a number of important qualitative differences between groups at varying risk of melanoma, and genders. Specifically, participants with a family history of melanoma believed genetic factors play an important role in melanoma causation; conveyed strong intentions to pursue genetic testing; and viewed the benefits of genetic testing as outweighing the limitations. Females appeared to endorse the testing of children more firmly than males, and males' intentions to pursue testing appeared more contingent on penetrance than females'. Across groups, the most preferred communication option was an informational video. CONCLUSION: Those at high risk of melanoma due to family history express a strong interest in predictive genetic testing.

Adult↗
PubMed1996

Childhood parental loss and alcoholism in women: a causal analysis using a twin-family design.

Childhood parental loss may be an important risk factor for psychiatric illness in adulthood. While this association has been carefully examined for depression, little is known about the role of parental loss in predisposing to alcoholism. We examined an epidemiological sample of female twin pairs with the same history of continuity or disruption in parent-child relationships (N=1018 pairs; mean age 30 years), using a range of definitions of alcoholism. Childhood parental loss through separation, but not death, substantially increased the risk in adulthood for all definitions of alcoholism. Furthermore, both paternal and maternal alcoholism substantially increased the probability of parental separation from their children. Proposing a structural equation twin-family model that incorporates childhood parental loss as a specified environmental risk factor, we examined how much of the association between childhood parental loss and alcoholism was causal (i.e. mediated by environmental factors) v. non-causal (mediated by genetic factors, with parental loss serving as an index of parental genetic susceptibility to alcoholism). Both the causal and non-causal paths were significant for all definitions of alcoholism. However, the causal-environmental pathway consistently accounted for most of the association. While a significant proportion of the association is due to non-causal genetic mechanisms, childhood parental loss (or the familial discord that precedes or follows it) is probably a direct and significant environmental risk factor for the development of alcoholism in women.

Adult↗
PubMed1995

[Application of genetic principles to the causal assessment of atherosclerosis].

The pathophysiological mechanisms responsible for the development of atherosclerosis are complex and influenced by numerous genetic factors [polygenic] as well as environmental factors. Specific disorders caused by single gene mutations [monogenic] may considerably enhance the risk for atherosclerosis. In such cases, other genes or environmental factors are often secondary importance. A detailed family history including a pedigree analysis may lead to the correct diagnosis; molecular genetic methods can confirm the clinical diagnosis. The association between a particular gene [candidate gene] and a disorder characterized by an increased risk for atherosclerosis can be verified indirectly by linkage analysis or directly by the detection of the gene mutation causing the disorder. Both approaches are based on the fact that a polymorphism used as a marker for a gene locus or a mutation responsible for a particular disorder may destroy or create a restriction site [restriction fragment length polymorphism, RFLP] or may modify the electrophoretic mobility of a fragment amplified by the polymerase chain reaction [PCR]. The latter property is the basis of the single-strand conformation polymorphism [SSCP] technique, followed by sequencing for the exact localization of the polymorphism or the mutation. Using these methods, other family members carrying the underlying gene defect can be identified and treated before the manifestation of their atherosclerotic lesions.

Animals↗
PubMed2026

Genetic evidence for a causal relationship between melatonin metabolism and depression.

To investigate the causal relevance of melatonin metabolism, which provides the biological basis for circulating melatonin levels, to specific depression symptom subtypes, we performed a targeted systematic review of melatonin metabolism pathways in the human brain and liver. Using two-sample Mendelian randomization (MR), we assessed the causal effects of metabolism pathways and/or individual genes on major depressive disorder (MDD) and nine symptom subtypes derived from Patient Health Questionnaire-9 (PHQ-9). Instrumental variables (IVs) were expression quantitative trait loci (eQTL) for eight individual genes, one synthesis route, and three degradation routes. Results were assessed using Bayesian colocalization and phenome-wide association analyses. At the pathway-level, the genetically proxied synthesis-route signal was associated with PHQ-9 Assessment 5 (PHQ9A5, OR: 0.89, 95% CI: 0.85-0.93), but sensitivity analyses suggested this association was primarily driven by TPH1 and may reflect serotonin-related biology. In contrast, higher brain melatonin degradation raised the risk of both PHQ9A1 (OR: 1.03, 95% CI: 1.02-1.04) and PHQ9A7 (OR: 1.03, 95% CI: 1.02-1.03). Within degradation, up-regulation of the kynurenine sub-pathway increased the odds of PHQ9A3 (OR: 1.05, 95% CI: 1.02-1.07), PHQ9A4 (OR&#xa0;=&#xa0;1.04, 95% CI: 1.02-1.06) and PHQ9A7 (OR: 1.05, 95% CI: 1.02-1.07). Gene-level analyses were largely concordant, except for SULT1A1, whose higher expression was genetically protective for PHQ9A3 but risk-increased for PHQ9A1 and PHQ9A4. Overall, these results demonstrate that melatonin metabolism exerts symptom-specific and pathway-specific causal effects on depression. A stratified view of melatonin's role may help optimize the application of exogenous melatonin supplementation.

Melatonin↗
PubMed2002

[SNP database and establishment of personalized medicine].

We are aiming to identify susceptibility genes for common or otherwise clinically relevant diseases of metabolism such as diabetes, asthma, and hypertension, and analyze the molecular causality. Although genetic and environmental factors play equally crucial roles in the pathogenesis of the common diseases of civilization, genetic factor is directly involved in the causality and molecular mechanism. The elucidation of molecular etiology provides specific molecular targets for therapeutic drugs even at the individual level. Thus our priority is analysis of the molecular causality of the common metabolic disorders of civilization. We will identify individual and group polymorphisms (SNPs) in the genome relevant to the treatment of individual patients closely related to susceptibility to disease, prognosis of disease, and responses to drugs. To determine the genetic susceptibilities, we apply genetic approaches such as linkage studies with affected sib-pairs and association studies using SNPs database together with haplotype analysis.

Databases, Genetic↗
PubMed2004

Genome coverage and sequence fidelity of phi29 polymerase-based multiple strand displacement whole genome amplification.

Major efforts are underway to systematically define the somatic and germline genetic variations causally associated with disease. Genome-wide genetic analysis of actual clinical samples is, however, limited by the paucity of genomic DNA available. Here we have tested the fidelity and genome representation of phi29 polymerase-based genome amplification (phi29MDA) using direct sequencing and high density oligonucleotide arrays probing >10,000 SNP alleles. Genome representation was comprehensive and estimated to be 99.82% complete, although six regions encompassing a maximum of 5.62 Mb failed to amplify. There was no degradation in the accuracy of SNP genotyping and, in direct sequencing experiments sampling 500,000 bp, the estimated error rate (9.5 x 10(-6)) was the same as in paired unamplified samples. The detection of cancer-associated loss of heterozygosity and copy number changes, including homozygous deletion and gene amplification, were similarly robust. These results suggest that phi29MDA yields high fidelity, near-complete genome representation suitable for high resolution genetic analysis.

Alleles↗