Genome-wide and phenome-wide studies provided insights into brain glymphatic system function and its clinical associations.

We applied an MRI technique diffusion tensor imaging along the perivascular space (DTI-ALPS) for assessing glymphatic system (GS) in a genome-wide association study (GWAS) and phenome-wide association study (PheWAS) of 40,486 European individuals. Exploratory analysis revealed 17 genetic loci significantly associating with the regional DTI-ALPS index. We found 58 genes, including and , which prioritized in the DTI-ALPS index subtypes and associated with neurodegenerative diseases.

Blood Calcium, Genetic Risk, and Risk of Incident Kidney Stone: A Population-Based Cohort Study.

Objective: To investigate the association between blood calcium concentration and incident kidney stone as well as to assess the role played by genetic susceptibility.

Methods: We performed a population-based cohort study based on participants from the UK Biobank. A multivariable Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% CIs of incident kidney stone for blood calcium level and polygenic risk score (PRS).

Associations of prior pulmonary tuberculosis with the incident COPD: a prospective cohort study.

Background: Prior pulmonary tuberculosis (PTB) might be associated with the development of chronic obstructive pulmonary disease (COPD). However, the impact of prior PTB on the risk of incident COPD has not been studied in a large prospective cohort study of the European population.

Objectives: This study aimed to investigate the association of prior PTB with the risk of COPD.

Integrative genome-wide analyses identify novel loci associated with kidney stones and provide insights into its genetic architecture.

Kidney stone disease (KSD) is a complex disorder with high heritability and prevalence. We performed a large genome-wide association study (GWAS) meta-analysis for KSD to date, including 720,199 individuals with 17,969 cases in European population. We identified 44 susceptibility loci, including 28 novel loci.

How can childhood maltreatment affect post-traumatic stress disorder in adult: Results from a composite null hypothesis perspective of mediation analysis.

Background: A greatly growing body of literature has revealed the mediating role of DNA methylation in the influence path from childhood maltreatment to psychiatric disorders such as post-traumatic stress disorder (PTSD) in adult. However, the statistical method is challenging and powerful mediation analyses regarding this issue are lacking.

Methods: To study how the maltreatment in childhood alters long-lasting DNA methylation changes which further affect PTSD in adult, we here carried out a gene-based mediation analysis from a perspective of composite null hypothesis in the Grady Trauma Project (352 participants and 16,565 genes) with childhood maltreatment as exposure, multiple DNA methylation sites as mediators, and PTSD or its relevant scores as outcome.

Genetic correlation and gene-based pleiotropy analysis for four major neurodegenerative diseases with summary statistics.

Recent genome-wide association studies suggested shared genetic components between neurodegenerative diseases. However, pleiotropic association patterns among them remain poorly understood. We here analyzed 4 major neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and found suggestively positive genetic correlation.

Detecting associated genes for complex traits shared across East Asian and European populations under the framework of composite null hypothesis testing.

Background: Detecting trans-ethnic common associated genetic loci can offer important insights into shared genetic components underlying complex diseases/traits across diverse continental populations. However, effective statistical methods for such a goal are currently lacking.

Methods: By leveraging summary statistics available from global-scale genome-wide association studies, we herein proposed a novel genetic overlap detection method called CONTO (COmposite Null hypothesis test for Trans-ethnic genetic Overlap) from the perspective of high-dimensional composite null hypothesis testing.

A comprehensive comparison of multilocus association methods with summary statistics in genome-wide association studies.

Background: Multilocus analysis on a set of single nucleotide polymorphisms (SNPs) pre-assigned within a gene constitutes a valuable complement to single-marker analysis by aggregating data on complex traits in a biologically meaningful way. However, despite the existence of a wide variety of SNP-set methods, few comprehensive comparison studies have been previously performed to evaluate the effectiveness of these methods.

Results: We herein sought to fill this knowledge gap by conducting a comprehensive empirical comparison for 22 commonly-used summary-statistics based SNP-set methods.

Assessing Causal Relationship Between Human Blood Metabolites and Five Neurodegenerative Diseases With GWAS Summary Statistics.

Neurodegenerative diseases (NDDs) are the leading cause of disability worldwide while their metabolic pathogenesis is unclear. Genome-wide association studies (GWASs) offer an unprecedented opportunity to untangle the relationship between metabolites and NDDs. By leveraging two-sample Mendelian randomization (MR) approaches and relying on GWASs summary statistics, we here explore the causal association between 486 metabolites and five NDDs including Alzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (PD), and multiple sclerosis (MS).

A comprehensive gene-centric pleiotropic association analysis for 14 psychiatric disorders with GWAS summary statistics.

Background: Recent genome-wide association studies (GWASs) have revealed the polygenic nature of psychiatric disorders and discovered a few of single-nucleotide polymorphisms (SNPs) associated with multiple psychiatric disorders. However, the extent and pattern of pleiotropy among distinct psychiatric disorders remain not completely clear.

Methods: We analyzed 14 psychiatric disorders using summary statistics available from the largest GWASs by far.

IUSMMT: Survival mediation analysis of gene expression with multiple DNA methylation exposures and its application to cancers of TCGA.

Effective and powerful survival mediation models are currently lacking. To partly fill such knowledge gap, we particularly focus on the mediation analysis that includes multiple DNA methylations acting as exposures, one gene expression as the mediator and one survival time as the outcome. We proposed IUSMMT (intersection-union survival mixture-adjusted mediation test) to effectively examine the existence of mediation effect by fitting an empirical three-component mixture null distribution.

Statistical methods for mediation analysis in the era of high-throughput genomics: Current successes and future challenges.

Mediation analysis investigates the intermediate mechanism through which an exposure exerts its influence on the outcome of interest. Mediation analysis is becoming increasingly popular in high-throughput genomics studies where a common goal is to identify molecular-level traits, such as gene expression or methylation, which actively mediate the genetic or environmental effects on the outcome. Mediation analysis in genomics studies is particularly challenging, however, thanks to the large number of potential mediators measured in these studies as well as the composite null nature of the mediation effect hypothesis.

Relationship between birth weight and chronic kidney disease: evidence from systematics review and two-sample Mendelian randomization analysis.

Observational studies showed an inverse association between birth weight and chronic kidney disease (CKD) in adulthood existed. However, whether such an association is causal remains fully elusive. Moreover, none of prior studies distinguished the direct fetal effect from the indirect maternal effect.

Are blood lipids risk factors for fracture? Integrative evidence from instrumental variable causal inference and mediation analysis using genetic data.

Background: The relationship between lipids and the risk of fracture is currently controversial and whether such association is causal remains elusive.

Methods: We performed two-sample inverse variance weighted (IVW) Mendelian randomization (MR) analyses to evaluate causal effects of four lipids (i.e.