Joint Association Analysis Research Articles

Association Between Cardiorespiratory Fitness and Trend of Age-Related Rise in Arterial Stiffness in Individuals With and Without Hypertension or Diabetes

Abstract BACKGROUND This study aimed to investigate whether higher cardiorespiratory fitness (CRF) can modify the trend of age-related rise in arterial stiffness in individuals with and without hypertension (HTN) or diabetes. METHODS The study included 4,935 participants who underwent maximal cardiopulmonary exercise testing with respiratory gas analysis in a health screening program. CRF was directly measured using peak oxygen uptake during the cardiopulmonary exercise test, while arterial stiffness was evaluated using brachial–ankle pulse wave velocity (baPWV). RESULTS Participants with high CRF levels had significantly lower baPWV compared with those with low CRF levels, regardless of HTN or diabetes status (P < 0.05). The trend of baPWV increased with age, but the rate of age-related increase in baPWV was lower in individuals with moderate-to-high CRF levels compared with those with low CRF levels, regardless of HTN or diabetes status. Joint association analysis indicated that the trend of age-related increase in baPWV was the lowest in fit individuals without HTN or diabetes compared with unfit individuals with HTN or diabetes (P < 0.01). However, the trend of age-related increase in baPWV was not attenuated in fit with HTN or diabetes compared with unfit with HTN or diabetes. CONCLUSIONS These findings suggest that higher CRF levels may mitigate the trend of age-related rise in arterial stiffness in individuals with and without HTN or diabetes. However, this attenuating trend appears more pronounced in individuals without HTN or diabetes.

Associations of exposure to organochlorine pesticides and polychlorinated biphenyls with chronic kidney disease among adults: the modifying effects of lifestyle.

Exposure to organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) has been reported to be associated with renal impairment and chronic kidney disease (CKD). Nevertheless, the research results thus far have exhibited inconsistency, and the effect of lifestyle on their association is not clear. In this study, we assessed the correlation between serum OCPs/PCBs and CKD and renal function indicators including estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) among 1721 Chinese adults. In order to further investigate the potential impact of lifestyle, we conducted joint associations of lifestyle and OCPs/PCBs on CKD. We found a negative correlation between p,p'-DDE and eGFR, while logistic regression results showed a positive correlation between PCB-153 and CKD (OR, 1.92; 95% CI, 1.21, 3.06). Quantile g-computation regression analyses showed that the association between co-exposure to OCPs/PCBs and CKD was not significant, but p,p'-DDE and PCB-153 were the main contributors to the negative and positive co-exposure effects of eGFR and CKD, respectively, which is consistent with the regression results. Participants with both relatively high PCB-153 exposure and an unhealthy lifestyle had the highest risk of CKD, in the joint association analysis. The observed associations were generally supported by the FAS-eGFR method. Our research findings suggest that exposure to OCPs/PCBs may be associated with decreased eGFR and increased prevalence of CKD in humans, and a healthy lifestyle can to some extent alleviate the adverse association between PCB-153 exposure and CKD.

JASPER: Fast, powerful, multitrait association testing in structured samples gives insight on pleiotropy in gene expression

Joint association analysis of multiple traits with multiple genetic variants can provide insight into genetic architecture and pleiotropy, improve trait prediction, and increase power for detecting association. Furthermore, some traits are naturally high-dimensional, e.g., images, networks, or longitudinally measured traits. Assessing significance for multitrait genetic association can be challenging, especially when the sample has population sub-structure and/or related individuals. Failure to adequately adjust for sample structure can lead to power loss and inflated type 1 error, and commonly used methods for assessing significance can work poorly with a large number of traits or be computationally slow. We developed JASPER, a fast, powerful, robust method for assessing significance of multitrait association with a set of genetic variants, in samples that have population sub-structure, admixture, and/or relatedness. In simulations, JASPER has higher power, better type 1 error control, and faster computation than existing methods, with the power and speed advantage of JASPER increasing with the number of traits. JASPER is potentially applicable to a wide range of association testing applications, including for multiple disease traits, expression traits, image-derived traits, and microbiome abundances. It allows for covariates, ascertainment, and rare variants and is robust to phenotype model misspecification. We apply JASPER to analyze gene expression in the Framingham Heart Study, where, compared to alternative approaches, JASPER finds more significant associations, including several that indicate pleiotropic effects, most of which replicate previous results, while others have not previously been reported. Our results demonstrate the promise of JASPER for powerful multitrait analysis in structured samples.

Shared Genetic Architectures between Coronary Artery Disease and Type 2 Diabetes Mellitus in East Asian and European Populations.

Coronary artery disease (CAD) is a common comorbidity of type 2 diabetes mellitus (T2DM). However, the pathophysiology connecting these two phenotypes remains to be further understood. Combined analysis in multi-ethnic populations can help contribute to deepening our understanding of biological mechanisms caused by shared genetic loci. We applied genetic correlation analysis and then performed conditional and joint association analyses in Chinese, Japanese, and European populations to identify the genetic variants jointly associated with CAD and T2DM. Next, the associations between genes and the two traits were also explored. Finally, fine-mapping and functional enrichment analysis were employed to identify the potential causal variants and pathways. Genetic correlation results indicated significant genetic overlap between CAD and T2DM in the three populations. Over 10,000 shared signals were identified, and 587 were shared by East Asian and European populations. Fifty-six novel shared genes were found to have significant effects on both CAD and T2DM. Most loci were fine-mapped to plausible causal variant sets. Several similarities and differences of the involved genes in GO terms and KEGG pathways were revealed across East Asian and European populations. These findings highlight the importance of immunoregulation, neuroregulation, heart development, and the regulation of glucose metabolism in shared etiological mechanisms between CAD and T2DM.

Adding salt to foods and risk of psoriasis: A prospective cohort study

BackgroundHigh salt intake may play a critical role in the etiology of psoriasis. Yet, evidence on the association of high salt intake with risk of psoriasis is limited. ObjectiveTo estimate the association between frequency of adding salt to foods and risk of psoriasis. MethodsWe conducted a prospective cohort study of 433,788 participants from the UK Biobank. Hazard ratios (HRs) and their 95 % confidence intervals (CIs) for risk of psoriasis in relation to frequency of adding salt to foods were estimated using multivariable Cox proportional hazards models. We further evaluated the joint association of adding salt to foods and genetic susceptibility with risk of psoriasis. We conducted a mediation analysis to assess how much of the effect of adding salt to foods on risk of psoriasis was mediated through several selected mediators. ResultsDuring a median of 14.0 years of follow-up, 4279 incident cases of psoriasis were identified. In the multivariable-adjusted model, a higher frequency of adding salt to foods was significantly associated with an increased risk of psoriasis (“always” versus “never/rarely” adding salt to foods, HR = 1.25, 95 % CI: 1.10, 1.41). The observed positive association was generally similar across subgroups. In the joint association analysis, we observed that participants with a high genetic risk (above the second tertile) and the highest frequency of adding salt to foods experienced 149 % higher risk of psoriasis, when compared with participants with a low genetic risk (below the first tertile) and the lowest frequency of adding salt to foods (HR = 2.49, 95 % CI: 2.05, 3.02). Mediation analysis revealed that 1.8 %–3.2 % of the positive association between frequency of adding salt and risk of psoriasis was statistically significantly mediated by obesity and inflammatory biomarkers such as C-reactive protein and systemic immune-inflammation index (all P values < 0.004). ConclusionsOur study demonstrated a positive association between frequency of adding salt to foods and risk of psoriasis. The positive association was independent of multiple other risk factors, and may be partially mediated through obesity and inflammation.

Association of Lifestyle Factors with Multimorbidity Risk in China: A National Representative Study

Multimorbidity significantly impacts health, well-being, and the economy; therefore, exploring notable factors associated with multimorbidity across all age groups is critical. For this investigation, we focused on the relationship between four lifestyle factors and multimorbidity risk. We recruited 11,031 Chinese citizens aged ≥ 12 years from 31 provinces between July 2021 and September 2021 using a quota sampling strategy to ensure that the socioeconomic characteristics (sex, age, rural–urban distribution) of those participating in this research were representative of national demographics. In the first stage, multivariable logistic regression models were utilized as a means of investigating the relationship between lifestyle factors and multimorbidity. Then, a multinomial logistic regression model was used with the aim of examining the Healthy Lifestyle Profile (HLP) related to the number of chronic diseases. Multivariable logistic regression models assessed the interaction effects and joint association among the four lifestyle factors. Overall, 18% of the participants had at least one disease, and 5.9% had multimorbidity. Approximately two-thirds of the participants were physically inactive, 40% had consumed alcohol, 39% were underweight or overweight, and 20% were or had been smokers. Participants who maintained one HLP showed a 34% lower multimorbidity risk (adjusted OR, 0.66; 95% CI, 0.48 to 0.92), while participants who maintained 4 HLP showed a 73% lower multimorbidity risk (adjusted OR, 0.27; 95% CI, 0.17 to 0.43), as compared to those who had 0 HLP. The joint association analysis revealed that participants with all four healthy lifestyle factors had 0.92 times lower odds of multimorbidity (95% CI: 0.90, 0.94) in comparison with the all-unhealthy reference cluster. Notably, individuals with a combination of healthy smoking status and healthy body weight had the highest minimized odds of multimorbidity (OR: [0.92], 95% CI: 0.91, 0.94). Common lifestyle habits, alone or in combination, are associated with multimorbidity risk. This study provides insights for public health programs to promote a healthy lifestyle at a younger age and to alleviate multimorbidity risk in older people.

Joint Linkage and Association Analysis Using GENEHUNTER-MODSCORE with an Application to Familial Pancreatic Cancer

Introduction: Joint linkage and association (JLA) analysis combines two disease gene mapping strategies: linkage information contained in families and association information contained in populations. Such a JLA analysis can increase mapping power, especially when the evidence for both linkage and association is low to moderate. Similarly, an association analysis based on haplotypes instead of single markers can increase mapping power when the association pattern is complex. Methods: In this paper, we present an extension to the GENEHUNTER-MODSCORE software package that enables a JLA analysis based on haplotypes and uses information from arbitrary pedigree types and unrelated individuals. Our new JLA method is an extension of the MOD score approach for linkage analysis, which allows the estimation of trait-model and linkage disequilibrium (LD) parameters, i.e., penetrance, disease-allele frequency, and haplotype frequencies. LD is modeled between alleles at a single diallelic disease locus and up to three diallelic test markers. Linkage information is contributed by additional multi-allelic flanking markers. We investigated the statistical properties of our JLA implementation using extensive simulations, and we compared our approach to another commonly used single-marker JLA test. To demonstrate the applicability of our new method in practice, we analyzed pedigree data from the German National Case Collection for Familial Pancreatic Cancer (FaPaCa). Results: Based on the simulated data, we demonstrated the validity of our JLA-MOD score analysis implementation and identified scenarios in which haplotype-based tests outperformed the single-marker test. The estimated trait-model and LD parameters were in good accordance with the simulated values. Our method outperformed another commonly used JLA single-marker test when the LD pattern was complex. The exploratory analysis of the FaPaCa families led to the identification of a promising genetic region on chromosome 22q13.33, which can serve as a starting point for future mutation analysis and molecular research in pancreatic cancer. Conclusion: Our newly proposed JLA-MOD score method proves to be a valuable gene mapping and characterization tool, especially when either linkage or association information alone provide insufficient power to identify the disease-causing genetic variants.

Pet Ownership, Living Alone, and Cognitive Decline Among Adults 50 Years and Older

It remains unclear whether pet ownership is associated with cognitive decline and to what extent pet ownership mitigates the association between living alone and cognitive decline. To explore the association of pet ownership with cognitive decline, the interaction between pet ownership and living alone, and the extent to which pet ownership mitigates the association between living alone and cognitive decline in older adults. This cohort study used data from waves 5 (June 2010 to July 2011) to 9 (from June 2018 to July 2019) in the English Longitudinal Study of Ageing. Participants included adults 50 years and older. Data were analyzed from April 1 to June 30, 2023. Pet ownership and living alone in wave 5. In waves 5 to 9, verbal memory and verbal fluency were assessed, and composite verbal cognition was further calculated. Of the 7945 participants included, the mean (SD) age was 66.3 (8.8) years, and 4446 (56.0%) were women. Pet ownership was associated with slower rates of decline in composite verbal cognition (β = 0.008 [95% CI, 0.002-0.014] SD/y), verbal memory (β = 0.006 [95% CI, 0.001-0.012] SD/y), and verbal fluency (β = 0.007 [95% CI, 0.001-0.013] SD/y). Three-way interaction tests showed that living alone was a significant modifier in all 3 associations. Stratified analyses showed that pet ownership was associated with slower rates of decline in composite verbal cognition (β = 0.023 [95% CI, 0.011-0.035] SD/y), verbal memory (β = 0.021 [95% CI, 0.008-0.034] SD/y), and verbal fluency (β = 0.018 [95% CI, 0.005-0.030] SD/y) among individuals living alone, but not among those living with others. Joint association analyses showed no significant difference in rates of decline in composite verbal cognition, verbal memory, or verbal fluency between pet owners living alone and pet owners living with others. In this cohort study, pet ownership was associated with slower rates of decline in verbal memory and verbal fluency among older adults living alone, but not among those living with others, and pet ownership offset the associations between living alone and declining rates in verbal memory and verbal fluency. Further studies are needed to assess whether pet ownership slows the rate of cognitive decline in older adults living alone.

Proteome Wide Association Studies of LRRK2 variants identify novel causal and druggable proteins for Parkinson’s disease

AbstractBackgroundLeucine‐rich repeat kinase 2 (LRRK2) common gene variants (tagged by rs76904798) are associated with Parkinson’s disease (PD) risk. In a previous study, we found that rs76904798 was associated with CSF GRN levels, but a comprehensive unbiased analysis of associated proteins remains incomplete due to prior focus on cis‐protein quantitative trait loci (pQTL). Using the largest aptamer‐based CSF proteomics study to date (7,006 aptamers (6,138 unique proteins) in 3,107 individuals), we performed a trans‐pQTL study to identify proteins associated with the LRRK2 variants and used additional mediation and pathway analyses to better understand downstream effects (Figure 1).MethodSNP selection using Conditional and Joint Association Analysis (GTCA‐COJO) and PLINK LD r2 scores identified 11 other independently associated SNPs. Fine mapping was performed between each significant aptamer and PD GWAS via proteome‐wide association studies (PWAS) and Mendelian randomization (MR). These aptamers were further analyzed based on PD risk association, brain cell‐type specificity, and gene pathway annotations.ResultOverall, 26 proteins passed FDR correction and eleven were implicated in PD prior like GRN and GPNMB. PWAS analyses using TWAS/FUSION also indicate 12 proteins were significant and positively associated with PD risk, such as novel proteins C1QTNF1 and SDCBP2, and half were validated by the PPMI data. MR analyses indicate that GRN, GPNMB, HLA‐DQA2, CD68, and LCT are also causal for PD risk (Table 1). Cell‐type enrichment analyses indicate microglia‐specific protein enrichment (Fold change: 7.35, P = 4.91×10−5). Enrichment analyses indicate enrichment for leukocyte activation (GO:0045321, P = 0.002) and microglial cell activation (GO:0001774, P = 0.003) pathways.ConclusionTrans‐pQTL can identify novel protein interactions in an unbiased manner. This study linked LRRK2 variants with both PD implicated (GRN, GPNMB) and novel (ITGB2, C1QTNF1) proteins that have support in our PWAS, MR, and PPMI differential protein level analyses. Microglia and lysosome enrichment support the previous observations regarding the importance of microglia and immune system function in the underlying pathobiology of PD (Figure 2). Our results suggest that the CSF concentrations of these proteins (such as GRN, GPNMB, C1QTNF1, and ITGB2) have potential as biomarkers for target engagement and disease progression modification in clinical trials that target LRRK2.

Associations of polychlorinated biphenyls and organochlorine pesticides with metabolic dysfunction-associated fatty liver disease among Chinese adults: Effect modification by lifestyle

Exposure to environmental pollutants and unhealthy lifestyles are key risk factors for metabolic dysfunction-associated fatty liver disease (MAFLD). While previous studies have suggested links between exposure to organochlorine pesticides (PCBs) and organochlorine pesticides (OCPs) and MAFLD, the results have been inconsistent. Furthermore, the combined effects of PCBs and OCPs on MAFLD and whether lifestyle factors can modify the associations remain unknown. Therefore, this study aimed to investigate the individual and joint effects of PCBs and OCPs on MAFLD and explore the potential modifying role of lifestyle. The study included 1923 participants from Wuhan, China. MAFLD was diagnosed based on ultrasonically diagnosed hepatic steatosis and the presence of overweight/obese, diabetes mellitus, or metabolic dysregulation. Healthy lifestyle score was determined by smoking, alcohol consumption, physical activity, and diet. Logistic regression and weighted quantile sum (WQS) were used to assess associations of individual and mixture of PCBs/OCPs with MAFLD. To explore the potential lifestyle modification, joint associations of PCBs/OCPs and lifestyle on MAFLD were conducted. Single-pollutant analysis showed positive associations of p,p′-DDE, β-HCH, PCB-153, and PCB-180 with MAFLD, with ORs (95% CIs) of 1.18 (1.05, 1.33), 1.57 (1.20, 2.05), 1.45 (1.14, 1.83), and 1.42 (1.12, 1.80), respectively. WQS regression demonstrated a harmful effect of PCBs/OCPs mixture on MAFLD (OR = 1.73, 95% CI = 1.24, 2.43), with β-HCH, p,p’-DDE, and PCB-180 being the major contributors. In the joint association analysis, participants with both high PCBs/OCPs exposure and unhealthy lifestyle have the highest odds of MAFLD. In conclusion, exposure to the mixture of PCBs and OCPs was positively correlated with MAFLD, and adopting a healthy lifestyle can mitigate the adverse impact.

Multitrait meta-analyses identify potential candidate genes for growth-related traits in Holstein heifers

Understanding the underlying pleiotropic relationships among growth and body size traits is important for refining breeding strategies in dairy cattle for optimal body size and growth rate. Therefore, we performed single-trait GWAS for monthly-recorded body weight (BW), hip height, body length, and chest girth from birth to 12 mo of age in Holstein animals, followed by stepwise multiple regression of independent or lowly-linked markers from GWAS loci using conditional and joint association analyses (COJO). Subsequently, we conducted a multitrait meta-analysis to detect pleiotropic markers. Based on the single-trait GWAS, we identified 170 significant SNPs, in which 59 of them remained significant after the COJO analyses. The most significant SNP, located at BTA7:3,676,741, explained 2.93% of the total phenotypic variance for BW6 (BW at 6 mo of age). We identified 17 SNPs with potential pleiotropic effects based on the multitrait meta-analyses, which resulted in 3 additional SNPs in comparison to those detected based on the single-trait GWAS. The identified quantitative trait loci regions overlap with genes known to influence human growth-related traits. According to positional and functional analyses, we proposed HMGA2, HNF4G, MED13L, BHLHE40, FRZB, DMP1, TRIB3, and GATAD2A as important candidate genes influencing the studied traits. The combination of single-trait GWAS and meta-analyses of GWAS results improved the efficiency of detecting associated SNPs, and provided new insights into the genetic mechanisms of growth and development in Holstein cattle.

Omega-3 index, cardiorespiratory fitness, and cognitive function in mid-age and older adults

Higher levels of omega-3 fatty acids in red blood cell membranes (omega-3 index or O3I) and cardiorespiratory fitness (CRF) are each associated with reduced cognitive impairment, but little research has examined the relationship between O3I and cognitive function while accounting for CRF. We analyzed cross-sectional data from 5,464 healthy men and women aged 55–85 years who had preventive medical examinations between 2009 and 2023. Primary exposures included O3I (<4.0%, 4.0–7.9%, or ≥ 8.0%) and age- and sex-based CRF quintile (1 = low, 2–3 = moderate, 4–5 = high). Cognitive impairment was defined as a Montreal Cognitive Assessment score of ≤ 25. We used Poisson regression to estimate relative risks (RR) of cognitive impairment, controlling for covariates. O3I < 4% was associated with increased cognitive impairment relative to ≥ 8.0% (RR, 1.21; 95% CI, 1.01–1.44) in a partially adjusted model. This association did not remain statistically significant in the fully adjusted model which included CRF. Low versus high CRF was associated with cognitive impairment (RR, 1.28; 95% CI, 1.07–1.53), independent of O3I and clinical biomarkers. The interaction between CRF and O3I was not significant (P = 0.8). In joint association analysis, risk of cognitive impairment was elevated with lower omega-3 index or CRF or both. Additional research is needed to fully understand the association between O3I and cognitive function at varying CRF levels.

Associations of urinary organophosphate esters metabolites and diet quality with nonalcoholic/metabolic dysfunction-associated fatty liver diseases in adults

Whether exposure to organophosphate esters (OPEs) is associated with metabolic dysfunction-associated fatty liver disease (MAFLD) and nonalcoholic fatty liver disease (NAFLD) remains unclear. A healthy diet is crucial to metabolic health and dietary intake is also an important route for OPEs exposure. However, the joint associations of OPEs, diet quality, and the effect modification by diet quality remain unknown. This study comprised 2618 adults with complete data on 6 urinary OPEs metabolites, 24 h dietary recalls, and definitions of NAFLD and MAFLD from the 2011–2018 National Health and Nutrition Examination Survey cycles. Multivariable binary logistic regression was applied to assess the associations of OPEs metabolites with NAFLD, MAFLD, and components of MAFLD. We also adopted the quantile g-Computation method to examine the associations of OPEs metabolites mixture. Our results revealed that OPEs metabolites mixture and three individual metabolites [i.e., bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis(2-chloroethyl) phosphate, and diphenyl phosphate] were significantly and positively associated with NAFLD and MAFLD (P-trend<0.001), with BDCIPP being identified as the dominant metabolite, whereas the 4 diet quality scores were monotonically and inversely associated with both MAFLD and NAFLD (P-trend<0.001). Of note, 4 diet quality scores were by and large negatively associated with BDCIPP, but not with other OPEs metabolites. Joint association analyses revealed that individuals with higher diet quality and lower BDCIPP concentration tend to have lower odds of having MAFLD and NAFLD in comparison with people in the low diet quality and high BDCIPP group, but the associations of BDCIPP were not modified by diet quality. Our findings suggest that certain OPEs metabolites and diet quality exhibited opposing associations with both MAFLD and NAFLD. Individuals adherent to a healthier diet may have a lower level of certain OPEs metabolites, and thus could have lower odds of having NAFLD and MAFLD.

Association of accelerometer-derived circadian abnormalities and genetic risk with incidence of atrial fibrillation

Evidence suggests potential links between circadian rhythm and atrial fibrillation (AF). However, whether circadian disruption can predict the onset of AF in the general population remains largely unknown. We aim to investigate the association of accelerometer-measured circadian rest-activity rhythm (CRAR, the most prominent circadian rhythm in humans) with the risk of AF, and examine joint associations and potential interactions of CRAR and genetic susceptibility with AF incidence. We include 62,927 white British participants of UK Biobank without AF at baseline. CRAR characteristics, including amplitude (strength), acrophase (timing of peak activity), pseudo-F (robustness), and mesor (height), are derived by applying an extended cosine model. Genetic risk is assessed with polygenic risk scores. The outcome is the incidence of AF. During a median follow-up of 6.16 years, 1920 participants developed AF. Low amplitude [hazard ratio (HR): 1.41, 95% confidence interval (CI): 1.25–1.58], delayed acrophase (HR: 1.24, 95% CI: 1.10–1.39), and low mesor (HR: 1.36, 95% CI: 1.21–1.52), but not low pseudo-F, are significantly associated with a higher risk of AF. No significant interactions between CRAR characteristics and genetic risk are observed. Joint association analyses reveal that participants with unfavourable CRAR characteristics and high genetic risk yield the highest risk of incident AF. These associations are robust after controlling for multiple testing and in a series of sensitivity analyses. Accelerometer-measured CRAR abnormalities, characterized by decreased strength and height, and later timing of peak activity of circadian rhythm, are associated with a higher risk of AF in the general population.

Abstract P327: Device-Measured Sedentary Behavior and Risk of 1-Year Hospital Readmission After Suspected Acute Coronary Syndrome

Background: Patients hospitalized with acute coronary syndrome (ACS) have an increased risk of a readmission during the first year after discharge; necessitating a need to identify modifiable therapeutic targets to improve outcomes. While moderate to vigorous physical activity (MVPA) has been a hallmark of secondary prevention efforts to prevent hospital readmission, sedentary behavior (SB) has emerged as a potentially unique and clinically important aspect of the physical activity profile. Yet, little is known regarding whether SB is associated with hospital readmission in ACS patients independent from or in addition to MVPA levels. Purpose: To examine the association between device-measured SB and risk of 1-year hospital readmission among patients evaluated for ACS, independent of MVPA. Methods: Patients (n=603, 47.8% female, 62.5±13.0 yrs) evaluated in the emergency department for ACS were fitted with a GENEActiv accelerometer in-hospital and were instructed to wear the device on their non-dominant wrist continuously in-hospital and for 30 days post-discharge. Hospital readmissions were ascertained by proactively searching medical records for any possible hospitalizations and by contacting participants or their closest contacts at 1- and 12-months follow-up; with supporting documentation secured from hospital medical records. Results: Over 1-year follow-up, 281 (46.6%) patients were readmitted. SB was associated with increased risk of 1-year hospital readmission after adjusting for socio-demographic factors, comorbidities, and disease severity indicators [HR per 1-hour per day increase in SB= 1.09, 95% CI: 1.01, 1.18]. The association remained significant after further adjusting for MVPA [HR per 1-hour per day increase in SB= 1.11, 95% CI: 1.02, 1.22]. In joint association analyses, high sedentary time in combination with low MVPA was associated with the greatest risk of 1-year hospital readmission in a fully adjusted model (HR: 2.18; 95%: CI: 1.44, 3.31) compared to the referent group (low SB/high MVPA). However, even among participants with higher levels of MVPA; high sedentary time was associated with a greater risk of 1-year re-hospitalization (HR: 1.54; 95% CI: 1.05, 2.27). For participants with low MVPA and low sedentary time, no significant association was observed (HR: 1.37; 95% CI: 0.84, 2.21). Conclusions: SB was associated with an increased risk of 1-year hospital readmission among patients evaluated for ACS. This increased risk was independent of MVPA and was not eliminated by high levels of MVPA. Implications of this study suggest that reducing SB should be considered as a modifiable therapeutic target in addition to MVPA to improve outcomes in ACS survivors.

Machine Learning for Brain Imaging Genomics Methods: A Review

In the past decade, multimodal neuroimaging and genomic techniques have been increasingly developed. As an interdisciplinary topic, brain imaging genomics is devoted to evaluating and characterizing genetic variants in individuals that influence phenotypic measures derived from structural and functional brain imaging. This technique is capable of revealing the complex mechanisms by macroscopic intermediates from the genetic level to cognition and psychiatric disorders in humans. It is well known that machine learning is a powerful tool in the data-driven association studies, which can fully utilize priori knowledge (intercorrelated structure information among imaging and genetic data) for association modelling. In addition, the association study is able to find the association between risk genes and brain structure or function so that a better mechanistic understanding of behaviors or disordered brain functions is explored. In this paper, the related background and fundamental work in imaging genomics are first reviewed. Then, we show the univariate learning approaches for association analysis, summarize the main idea and modelling in genetic-imaging association studies based on multivariate machine learning, and present methods for joint association analysis and outcome prediction. Finally, this paper discusses some prospects for future work.

Genetic factors associated with serum amylase in a Japanese population: combined analysis of copy-number and single-nucleotide variants

Amylase activity and levels in humans are heritable quantitative traits. Although many studies exist on the effects of copy-number variants (CNVs) in amylase genes (AMY) on human phenotypes, such as body mass index (BMI), the genetic factors controlling interindividual variation in amylase levels remain poorly understood. Here, we conducted a genome-wide association study (GWAS) of serum amylase levels (SAL) in 814 Japanese individuals to identify associated single-nucleotide variants (SNVs), after adjusting for non-genetic factors. Diploid copy numbers (CN) of AMY (AMY1, AMY2A, and AMY2B) were measured using droplet digital PCR to examine the association between each diploid CN and SAL. We further assessed the relative contribution of the GWAS-lead SNV and AMY CNVs to SAL. GWAS identified 14 significant SNVs (p < 5 × 10−8) within a linkage disequilibrium block near the AMY cluster on chromosome 1. The association analyses of AMY CNVs and SAL showed a significant association between AMY1 diploid CN and SAL (p = 1.89 × 10−19), while no significant association with SAL was found for AMY2A CN (p = 0.54) or AMY2B CN (p = 0.15). In a joint association analysis with SAL using the GWAS-lead SNV and AMY1 diploid CN, AMY1 CN remained significant (p = 5.4 ×10−13), while the association of the lead SNV was marginal (p = 0.08). We also found no association between AMY1 diploid CN and BMI (p = 0.14). Our results indicate that AMY1 CNV is the major genetic factor for Japanese SAL, with no significant association with BMI.

Independent and Joint Associations of Exercise Blood Pressure and Cardiorespiratory Fitness With the Risk of Cardiovascular Mortality.

We tested the hypothesis that an exaggerated systolic blood pressure (ESBP) at maximal exercise workload would be associated with an increased risk of cardiovascular disease (CVD) mortality, and that high cardiorespiratory fitness (CRF) attenuates this risk. This prospective study was based on the general population sample of 1,481 men (aged 42-61 years) who did not have a history of CVD at baseline and were followed up in the Kuopio Ischemic Heart Disease cohort study. Exercise blood pressure and CRF were measured during cardiopulmonary exercise testing, and an ESBP was defined by a peak systolic blood pressure ≥210 mm Hg and CRF categorized as tertiles and unfit and fit groups. During a 26-year median follow-up, 231 CVD deaths occurred. After adjusting for potential confounding factors, an ESBP was associated with an increased risk of CVD mortality (hazard ratio [HR] 1.43, 95% confidence interval: 1.06-1.94), while the highest tertile of CRF was associated with a lower risk of CVD mortality (HR 0.64, 0.43-0.95). In the joint association analyses of ESBP and CRF, ≥210 mm Hg-unfit group had a higher risk of CVD mortality (HR 1.70, 1.02-2.83), but also ≥210 mm Hg-fit group had an increased risk of CVD death (HR 1.95, 1.20-3.18) compared with their <210 mm Hg-fit counterparts. These results indicate that an ESBP is independently associated with an increased risk of CVD death, but moderate-to-high levels of CRF does not attenuate CVD mortality risk in those with ESBP.

Joint association of alcohol consumption and adiposity with alcohol- and obesity-related cancer in a population sample of 399,575 UK adults.

Obesity and alcohol consumption are both important modifiable risk factors for cancer. We examined the joint association of adiposity and alcohol consumption with alcohol- and obesity-related cancer incidence. This prospective cohort study included cancer-free UK Biobank participants aged 40-69 years. Alcohol consumption was categorised based on current UK guidelines into four groups. We defined three markers of adiposity: body fat percentage (BF %), waist circumference and BMI and categorised each into three groups. We derived a joint alcohol consumption and adiposity marker variable with twelve mutually exclusive categories. Among 399575 participants, 17617 developed alcohol-related cancer and 20214 developed obesity-related cancer over an average follow-up of 11·8 (SD 0·9) years. We found relatively weak evidence of independent associations of alcohol consumption with cancer outcomes. However, the joint association analyses showed that across all adiposity markers, above guideline drinkers who were in the top two adiposity groups had elevated cancer incidence risk (e.g. HR for alcohol-related cancer was 1·53 (95 % CI (1·24, 1·90)) for within guideline drinkers and 1·61 (95 % CI (1·30, 2·00)) for above guideline drinkers among participants who were in the top tertile BF %. Regardless of alcohol consumption status, the risk of obesity-related cancer increased with higher adiposity in a dose-response manner within alcohol consumption categories. Our study provides guidance for public health priorities aimed at lowering population cancer risk via two key modifiable risk factors.

Sedentary Behavior and Physical Functioning in Middle-Age and Older Adults Living in the United States: The Reasons for Geographic and Racial Differences in Stroke Study.

Sedentary behavior is associated with poor physical function in older adults, which can lead to accelerated skeletal muscle aging (sarcopenia) and premature mortality. We examined the independent and joint effects of sedentary behavior and moderate to vigorous intensity physical activity (MVPA) with measures of physical functioning. We studied 5408 participants in the REasons for Geographic and Racial Differences in Stroke study who wore a hip-mounted accelerometer over seven consecutive days (2009-2013) and had self-reported and directly observed physical function (time walk, chair stand test) measured during an in-home visit conducted from 2013 to 2016. Greater sedentary time was significantly associated with poorer chair stand and timed walk scores. Substituting 30 min of sedentary time with 30 min of MVPA was associated with significant improvements in chair stands (β -0.57; P = 0.007) and timed walk (β -0.36; P = 0.01). Similar, but less robust, findings were observed for reallocations of sedentary time to light-intensity physical activity. In joint association analyses, high sedentary time in combination with low MVPA (but not in combination with high MVPA) was associated with poorer physical function compared with the referent group (low sedentary time/high MVPA; P < 0.001 for all). Greater time spent being sedentary was associated with worse physical functioning outcomes. However, reallocations of sedentary time to light-intensity physical activity, and especially MVPA, were associated with more favorable physical functioning. Interventions aimed to increase MVPA and reduce sedentary behavior should be a priority, especially among populations at greatest risk for sarcopenia and physical function decline.