United Kingdom Biobank Research Articles

Relationships between body fat distribution and metabolic syndrome traits and outcomes: A mendelian randomization study.

Obesity is a complex, multifactorial disease associated with substantial morbidity and mortality worldwide. Although it is frequently assessed using BMI, many epidemiological studies have shown links between body fat distribution and obesity-related outcomes. This study examined the relationships between body fat distribution and metabolic syndrome traits using Mendelian Randomization (MR). Genetic variants associated with visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), and gluteofemoral adipose tissue (GFAT), as well as their relative ratios, were identified from a genome wide association study (GWAS) performed with the United Kingdom BioBank. GWAS summary statistics for traits and outcomes related to metabolic syndrome were obtained from the IEU Open GWAS Project. Two-sample MR and BMI-controlled multivariable MR (MVMR) were performed to examine relationships between each body fat measure and ratio with the outcomes. Increases in absolute GFAT were associated with a protective cardiometabolic profile, including lower low density lipoprotein cholesterol (β: -0.19, [95% CI: -0.28, -0.10], p < 0.001), higher high density lipoprotein cholesterol (β: 0.23, [95% CI: 0.03, 0.43], p = 0.025), lower triglycerides (β: -0.28, [95% CI: -0.45, -0.10], p = 0.0021), and decreased systolic (β: -1.65, [95% CI: -2.69, -0.61], p = 0.0019) and diastolic blood pressures (β: -0.95, [95% CI: -1.65, -0.25], p = 0.0075). These relationships were largely maintained in BMI-controlled MVMR analyses. Decreases in relative GFAT were linked with a worse cardiometabolic profile, with higher levels of detrimental lipids and increases in systolic and diastolic blood pressures. A MR analysis of ASAT, GFAT, and VAT depots and their relative ratios with metabolic syndrome related traits and outcomes revealed that increased absolute and relative GFAT were associated with a favorable cardiometabolic profile independently of BMI. These associations highlight the importance of body fat distribution in obesity and more precise means to categorize obesity beyond BMI.

Association of unsweetened and sweetened tea consumption with the risk of new-onset chronic kidney disease: Findings from UK Biobank and Coronary Artery Risk Development in Young Adults (CARDIA) study.

The association between tea consumption and chronic kidney disease (CKD) remained inconsistent. We aimed to evaluate the association of tea consumption with new-onset CKD and examine the effects of common additives (milk and sweeteners) and genetic variations in caffeine metabolism on the association. 176 038 and 3104 participants free of CKD at baseline in the United Kingdom Biobank (UK Biobank) and Coronary Artery Risk Development in Young Adults (CARDIA) study were included, respectively. Dietary information was collected using 24-hour dietary recall questionnaires. The study outcome was new-onset CKD. In the UK Biobank, during a median follow-up of 12.13 years, 3535 (2.01%) participants developed CKD. Compared with tea non-consumers, the risk of new-onset CKD was significantly lower in unsweetened tea consumers (hazard ratio (HR) = 0.84, 95% confidence interval (CI) = 0.76-0.93), but not in sweetened tea consumers (HR = 0.96, 95% CI = 0.85-1.08), regardless of whether milk was added to tea. Accordingly, relative to tea non-consumers, the adjusted HRs (95% CIs) of new-onset CKD for participants who reported drinking unsweetened tea 1.5 or fewer, >1.5 to 2.5, >2.5 to 3.5, >3.5 to 4.5, and >4.5 drinks/d were HR = 0.86, 95% CI = 0.75-0.99; HR = 0.88, 95% CI = 0.78-1.00; HR = 0.83, 95% CI = 0.73-0.94; HR = 0.83, 95% CI = 0.72-0.95; and HR = 0.86, 95% CI = 0.75-0.99. Moreover, the association of unsweetened tea consumption with new-onset CKD was stronger among those with faster genetically predicted caffeine metabolism levels, although the interaction was insignificant (P-value interaction = 0.768). Consistently, in the CARDIA study, compared with tea non-consumers, a significantly lower risk of new-onset CKD was found in unsweetened tea consumers (HR = 0.80, 95% CI = 0.65-0.98) but not in sweetened tea consumers (HR = 0.97, 95% CI = 0.70-1.34). Compared with tea non-consumers, consumption of unsweetened tea, but not sweetened tea, was significantly associated with a lower risk of new-onset CKD, regardless of whether milk was added.

Association between age at first birth and postpartum depression: A two-sample mendelian randomization analysis

BackgroundPrevious observational research has documented an association between age at first childbirth (AFB) and postpartum depression (PPD). However, the causal relationship remains unclear. This study aimed to assess the causal effects of AFB on PPD using a two-sample Mendelian randomization (MR) analysis. MethodsThree sets of instrumental variables were obtained from the United Kingdom Biobank (UK Biobank), Neale Lab consortium and a meta-analysis of genome-wide association studies (GWAS). Single-nucleotide polymorphisms (SNPs) associated with the PPD phenotype were obtained from the Finngen consortium, which included 13,657 cases and 236,178 controls. Inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger methods to evaluate causal effects. Heterogeneity was assessed using Cochran's Q test and funnel plots. Horizontal pleiotropy and sensitivity were assessed using the MR-Egger intercept test and “leave-one-out” analysis, respectively. Further meta-analysis was performed to validate the robustness of this relationship. Additionally, the potential mediating effects of risk factors associated with PPD were analyzed. ResultsStrong causal effects between AFB and PPD was found in both IVW and weighted median methods, which was further supported by meta-analysis (IVW, odds ratio [OR] 0.59 [95% confidence interval (CI) 0.36–0.96, p = 0.03]; weighted median, OR 0.59 [95% CI 0.37–0.95, p = 0.03]). The power of the MR supports the robustness of the findings. Heterogeneity or horizontal pleiotropy was not observed. Major depressive disorders, family income levels, and marital stress were identified as potential mediating factors in the causal relationships. ConclusionResults of MR analysis supported the causal effect of increased AFB in reducing the risk for PPD.

Mouse and human studies support DSTYK loss of function as a low-penetrance and variable expressivity risk factor for congenital urinary tract anomalies

PurposePrevious work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYK variants. MethodsWe phenotypically characterized Dstyk knockout mice of 3 separate inbred backgrounds and re-analyzed the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to as “SSV” below). DSTYK loss of function (LOF) and SSVs were annotated in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis vs controls. A phenome-wide association study analysis was also performed using United Kingdom Biobank (UKBB) data. ResultsResults demonstrate ∼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk–/– mice. Phenotypic penetrance increased to ∼40% in C3H/HeJ mutants, with mild-to-moderate severity. Re-analysis of the original family segregating the rare SSV showed low penetrance (43.8%) and no alternative genetic causes for CAKUT. LOF DSTYK variants burden showed significant excess for CAKUT and epilepsy vs controls and an exploratory phenome-wide association study supported association with neurological disorders. ConclusionThese data support causality for DSTYK LOF variants and highlights the need for large-scale sequencing studies (here >200,000 cases) to accurately assess causality for genes and variants to lowly penetrant traits with common population prevalence.

Bidirectional Association Between Cardiovascular Disease and Lung Cancer in a Prospective Cohort Study

IntroductionThe study aimed to prospectively investigate the bidirectional association between cardiovascular disease (CVD) and lung cancer, and whether this association differs across genetic risk levels. MethodsThis study prospectively followed 455,804 participants from the United Kingdom Biobank cohort who were free of lung cancer at baseline. Cox proportional hazard models were used to estimate the hazard ratio (HR) for incident lung cancer according to CVD status. In parallel, similar approaches were used to assess the risk of incident CVD according to lung cancer status among 478,756 participants free of CVD at baseline. The bidirectional causal relations between these conditions were assessed using Mendelian randomization analysis. Besides, polygenic risk scores were estimated by integrating genome-wide association studies identified risk variants. ResultsDuring 4,007,477 person-years of follow-up, 2006 incident lung cancer cases were documented. Compared with participants without CVD, those with CVD had HRs (95% confidence interval [CI]) of 1.49 (1.30–1.71) for NSCLC, 1.80 (1.39–2.34) for lung squamous cell carcinoma (LUSC), and 1.25 (1.01–1.56) for lung adenocarcinoma (LUAD). After stratification by smoking status, significant associations of CVD with lung cancer risk were observed in former smokers (HR = 1.44, 95% CI: 1.20–1.74) and current smokers (HR = 1.38, 95% CI: 1.13–1.69), but not in never-smokers (HR = 0.98, 95% CI: 0.60–1.61). In addition, CVD was associated with lung cancer risk across each genetic risk level (pheterogeneity = 0.336). In the second analysis, 32,974 incident CVD cases were recorded. Compared with those without lung cancer, the HRs (95% CI) for CVD were 2.33 (1.29–4.21) in NSCLC, 3.66 (1.65–8.14) in LUAD, and 1.98 (0.64–6.14) in LUSC. In particular, participants with lung cancer had a high risk of incident CVD at a high genetic risk level (HR = 3.79, 95% CI: 1.57–9.13). No causal relations between these conditions were observed in Mendelian randomization analysis. ConclusionsCVD is associated with an increased risk of NSCLC including LUSC and LUAD. NSCLC, particularly LUAD, is associated with a higher CVD risk. Awareness of this bidirectional association may improve prevention and treatment strategies for both diseases. Future clinical demands will require a greater focus on cardiac oncology.

Univariable and multivariable Mendelian randomization investigating the effects of telomere length on the risk of adverse pregnancy outcomes.

Numerous observational studies have revealed a correlation between telomere length (TL) and adverse pregnancy outcomes (APOs). However, the impacts of TL on APOs are still unclear. Mendelian randomization (MR) was carried out using summary data from genome-wide association studies (GWAS). Inverse variance weighted (IVW) was employed as the primary analysis to explore the causal relationship between TL and APOs. The exposure data came from a GWAS dataset of IEU analysis of the United Kingdom Biobank phenotypes consisting of 472,174 European participants. Summary-level data for five APOs were obtained from the GWAS datasets of the FinnGen consortium. We also performed multivariate MR (MVMR), adjusting for smoking, alcohol intake, body mass index (BMI), and number of live births. In addition, we conducted a series of rigorous analyses to further examine the validity of our MR findings. After Bonferroni correction and rigorous quality control, univariable MR (UVMR) demonstrated that a shorter TL was significantly associated with an increased risk of spontaneous abortion (SA) (odds ratio [OR]: 0.815; 95% confidence interval [CI]: 0.714-0.930; P = 0.002) and preterm birth (PTB) (OR: 0.758; 95% CI: 0.632-0.908; P = 0.003) in the IVW model. There was a nominally significant relationship between TL and preeclampsia (PE) in the IVW model (OR: 0.799; 95% CI: 0.651-0.979; P = 0.031). However, no significant association was found between TL and gestational diabetes mellitus (GDM) (OR: 0.950; 95% CI: 0.804-1.122; P = 0.543) or fetal growth restriction (FGR) (OR: 1.187; 95% CI: 0.901-1.565; P = 0.223) among the five statistical models. Furthermore, we did not find a significant causal effect of APOs on TL in the reverse MR analysis. MVMR analysis showed that the causal effects of TL on SA remained significant after accounting for smoking, alcohol intake, BMI, and number of live births. Our MR study provides robust evidence that shorter telomeres were associated with an increased risk of SA. Further work is necessary to investigate the potential mechanisms. UVMR and MVMR findings showed limited evidence that TL affects the risk of PTB, PE, GDM, and FGR, illustrating that the outcomes of previous observational studies may have been confounded.

Heritable Traits and Lung Cancer Risk: A Two-Sample Mendelian Randomization Study.

Lung cancer is a complex polygenic disorder. Analysis with Mendelian randomization (MR) allows for genetically predicted risks to be estimated between exposures and outcomes. We analyzed 345 heritable traits from the United Kingdom Biobank and estimated their associated effects on lung cancer outcomes using two sample MR. In addition to estimating effects with overall lung cancer, adenocarcinoma, small cell lung cancer, and squamous cell lung cancers, we performed conditional effect modeling with multivariate MR (MVMR) and the traits of alcohol use, smoking initiation, average pre-tax income, and educational attainment. Univariate MR provided evidence for increased age at first sexual intercourse (OR, 0.55; P = 6.15×10-13), educational attainment (OR, 0.24; P = 1.07×10-19), average household income (OR, 0.58; P = 7.85×10-05), and alcohol usually taken with meals (OR, 0.19; P = 1.06×10-06) associating with decreased odds of overall lung cancer development. In contrast, a lack of additional educational attainment (OR, 8.00; P = 3.48×10-12), body mass index (OR, 1.28; P = 9.00×10-08), pack years smoking as a proportion of life span (OR, 9.93; P = 7.96×10-12), and weekly beer intake (OR, 3.48; P = 4.08×10-07) were associated with an increased risk of overall lung cancer development. Many heritable traits associated with an increased or inverse risk of lung cancer development. Effects vary based on histologic subtype and conditional third trait exposures. We identified several heritable traits and presented their genetically predictable impact on lung cancer development, providing valuable insights for consideration.

Prevalence and significance of DDX41 gene variants in the general population

AbstractGerm line variants in the DDX41 gene have been linked to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) development. However, the risks associated with different variants remain unknown, as do the basis of their leukemogenic properties, impact on steady-state hematopoiesis, and links to other cancers. Here, we investigate the frequency and significance of DDX41 variants in 454 792 United Kingdom Biobank (UKB) participants and identify 452 unique nonsynonymous DNA variants in 3538 (1/129) individuals. Many were novel, and the prevalence of most varied markedly by ancestry. Among the 1059 individuals with germ line pathogenic variants (DDX41-GPV) 34 developed MDS/AML (odds ratio, 12.3 vs noncarriers). Of these, 7 of 218 had start-lost, 22 of 584 had truncating, and 5 of 257 had missense (odds ratios: 12.9, 15.1, and 7.5, respectively). Using multivariate logistic regression, we found significant associations of DDX41-GPV with MDS, AML, and family history of leukemia but not lymphoma, myeloproliferative neoplasms, or other cancers. We also report that DDX41-GPV carriers do not have an increased prevalence of clonal hematopoiesis (CH). In fact, CH was significantly more common before sporadic vs DDX41-mutant MDS/AML, revealing distinct evolutionary paths. Furthermore, somatic mutation rates did not differ between sporadic and DDX41-mutant AML genomes, ruling out genomic instability as a driver of the latter. Finally, we found that higher mean red cell volume (MCV) and somatic DDX41 mutations in blood DNA identify DDX41-GPV carriers at increased MDS/AML risk. Collectively, our findings give new insights into the prevalence and cognate risks associated with DDX41 variants, as well as the clonal evolution and early detection of DDX41-mutant MDS/AML.

Nut consumption is associated with a lower risk of depression in adults: A prospective analysis with data from the UK Biobank cohort

Evidence on the association between nut consumption and depression is mainly based on cross-sectional studies. This study aims to analyse whether nut consumption is prospectively associated with the risk of depression in adults. This study was conducted using the United Kingdom (UK) Biobank resource. Data from middle-aged and older UK adults who participated in this cohort between 2007-2012 (baseline) and 2013-2020 (follow-up) were analysed. Baseline information on nut consumption was obtained with the Oxford WebQ 24-h questionnaire. Depression, defined as a self-reported physician diagnosis of depression or antidepressant use, was assessed at baseline and follow-up. Hazard regression models estimating the predictive ability of nut consumption for the risk of developing depression were adjusted for sociodemographic, lifestyle, and health confounders. A total of 13,504 participants (mean age 57.5±7.2 years, 50.7% female) free of depression at baseline were included in the analyses. After a mean follow-up of 5.3±2.4 years, 1122 (8.3%) incident cases of depression were identified. Compared with no nut consumption, the daily consumption of >0 to 1 serving of 30g of nuts was associated with a lower risk of depression (hazard ratio, HR=0.83; 95% confidence interval, CI: 0.71-0.97) regardless of all potential confounders considered. In stratified analyses, a decreased risk of depression was more clearly observed in UK adults with adequate weight control, a healthy lifestyle, and better health status than in their counterparts (p<0.05). Low-to-moderate nut consumption (>0 to 1 serving of 30g/day) was associated with a 17% lower risk of depression during a 5.3-year follow-up compared with no nut consumption in a large sample of middle-aged and older UK adults. This protective association is enhanced in the absence of other known risk factors for depression.

25-hydroxyvitamin D concentrations and risk of incident dementia, mild cognitive impairment, and delirium in 443,427 UK Biobank participants

This study aimed to investigate the association between serum 25-hydroxyvitamin D (25(OH)D) levels and dementia, mild cognitive impairment (MCI), and delirium. Participants from the United Kingdom (UK) Biobank with complete information on serum 25(OH)D concentrations were enrolled. Dementia, MCI and delirium were defined using the UK Biobank algorithm. 443,427 participants with a mean (standard deviation) age of 56.8 (8.0) years were included in this study. Based on Cox regression models, serum 25(OH)D concentrations were inversely associated with the risk of dementia, MCI, and delirium in a dose-dependent manner after adjusting for demographics (P-trend <0.001). In comparison with 25(OH)D levels less than 32.4 nmol/L, participants with the highest 25(OH)D levels (i.e., >64.4 nmol/L) had the lowest risk of dementia (hazards ratio [HR]: 0.58, 95% confidence interval [CI] 0.49–0.69, P<0.001), MCI (HR: 0.55, 95% CI 0.37–0.84, P=0.005), and delirium (HR: 0.63, 95% CI 0.51–0.79, P<0.001). These results were consistent with the sensitivity analysis, in which participants with events occurring within the first two years of follow-up were excluded. This study found that a lower serum 25(OH)D concentration was significantly associated with a higher risk of dementia (including Alzheimer's disease and vascular dementia), MCI, and delirium.

The rs72613567:TA polymorphism in HSD17B13 is associated with survival benefit after development of hepatocellular carcinoma.

The influence of genetic factors on survival following a diagnosis of hepatocellular carcinoma (HCC) remains unclear. To assess whether genetic polymorphisms influencing the susceptibility to develop HCC are also associated with HCC prognosis. We included United Kingdom Biobank (UKB) participants diagnosed with HCC after study enrolment. The primary outcome was all-cause mortality. Patients were followed from the date of HCC diagnosis to death or the registry completion date. Five HCC susceptibility loci were investigated: rs738409 (PNPLA3), rs58542926 (TM6SF2); rs72613567 (HSD17B13); rs2242652 (TERT) and rs708113 (WNT3A). The associations between these genetic variants and HCC mortality risk were assessed using Cox regression, adjusted for age, sex, ethnicity, aetiology, severity of the underlying liver disease and receipt of curative HCC treatment. The final sample included 439 patients; 74% had either non-alcoholic fatty liver disease or alcohol-related liver disease. There were 321 deaths during a mean follow-up of 1.9 years per participant. Kaplan-Meier survival estimates at 1, 3 and 5 years were 53.2%, 31.2% and 22.6% respectively. In multivariate analysis, rs72613567:TA (HSD17B13) was the only genetic susceptibility variant significantly associated with all-cause mortality risk (aHR: 0.74; 95% CI: 0.61-0.90; p = 0.003). Other associated factors were Baveno stage 3-4 (aHR: 1.65; 95% CI: 1.05-2.59; p = 0.03) and HCC treatment with curative intent (aHR: 0.25; 95% CI: 0.17-0.37; p < 0.001). The rs72613567:TA polymorphism in HSD17B13 is not only associated with a reduction in the risk of developing HCC but with a survival benefit in HCC once established. Therapeutic inhibition of HSD17B13 may augment survival in individuals with HCC.

Association between gut microbiota and gastrointestinal cancer: a two-sample bi-directional Mendelian randomization study.

The gut microbiome is closely related to gastrointestinal (GI) cancer, but the causality of gut microbiome with GI cancer has yet to be fully established. We conducted this two-sample Mendelian randomization (MR) study to reveal the potential causal effect of gut microbiota on GI cancer. Summary-level genetic data of gut microbiome were derived from the MiBioGen consortium and the Dutch Microbiome Project. Summary statistics of six GI cancers were drawn from United Kingdom Biobank. Inverse-variance-weighted (IVW), MR-robust adjusted profile score (MR-RAPS), and weighted-median (WM) methods were used to evaluate the potential causal link between gut microbiota and GI cancer. In addition, we performed sensitivity analyses and reverse MR analyses. We identified potential causal associations between 21 bacterial taxa and GI cancers (values of p < 0.05 in all three MR methods). Among them, phylum Verrucomicrobia (OR: 0.17, 95% CI: 0.05-0.59, p = 0.005) retained a strong negative association with intrahepatic cholangiocarcinoma after the Bonferroni correction, whereas order Bacillales (OR: 1.67, 95% CI: 1.23-2.26, p = 0.001) retained a strong positive association with pancreatic cancer. Reverse MR analyses indicated that GI cancer was associated with 17 microbial taxa in all three MR methods, among them, a strong inverse association between colorectal cancer and family Clostridiaceae1 (OR: 0.91, 95% CI: 0.86-0.96, p = 0.001) was identified by Bonferroni correction. Our study implicates the potential causal effects of specific microbial taxa on GI cancer, potentially providing new insights into the prevention and treatment of GI cancer through specific gut bacteria.

Associations of 25-hydroxyvitamin D status and vitamin D supplementation use with mortality due to 18 frequent cancer types in the UK Biobank cohort

BackgroundAlthough the associations of serum 25-hydroxyvitamin D (25(OH)D) levels and vitamin D supplementation with total cancer mortality are well-known, evidence regarding the association of 25(OH)D and cancer site-specific mortality is predominantly limited to common cancer types, and most studies on vitamin D supplementation use have limitations on sample size and the adjustment of important confounding factors. MethodsWe used cause-specific Cox regression models adjusted for 48 covariates to assess the associations of vitamin D deficiency, insufficiency, and vitamin D supplementation use with mortality from any cancer and 18 specific cancers in 411,436 United Kingdom Biobank participants, aged 40–69 years. ResultsThe majority of the study population had either vitamin D deficiency (21.1%) or insufficiency (34.4%). Furthermore, 4.1% and 20.3% of the participants regularly took vitamin D or multivitamin supplements, respectively. During a median follow-up of 12.7 years, vitamin D deficiency was associated with significantly increased mortality from total cancer and four specific cancers: stomach (hazard ratio, 95% confidence interval: 1.42, 1.05–1.92), colorectal (1.27, 1.07–1.50), lung (1.24, 1.10–1.40), and prostate (1.36, 1.06–1.75). Vitamin D insufficiency was associated with increased colorectal (1.14, 1.00–1.30) and lung cancer mortality (1.19, 1.08–1.32). Compared to non-users, vitamin D use was associated with lower lung cancer (0.75, 0.60–0.95) and total cancer mortality. Multivitamin use was associated with lower mortality from melanoma (0.64, 0.43–0.97). ConclusionVitamin D deficiency and insufficiency were associated with increased mortality from multiple common cancers. The potential to reduce cancer mortality by vitamin D supplementation in populations with low 25(OH)D levels should be further explored.

Simultaneous multislice EPI prospective motion correction by real-time receiver phase correction and coil sensitivity map interpolation.

To improve the image reconstruction for prospective motion correction (PMC) of simultaneous multislice (SMS) EPI of the brain, an update of receiver phase and resampling of coil sensitivities are proposed and evaluated. A camera-based system was used to track head motion (3 translations and 3 rotations) and dynamically update the scanposition and orientation. We derived the change in receiver phase associated with a shifted field of view (FOV) and applied it in real-time to each k-space line of the EPI readout trains. Second, for the SMS reconstruction, we adapted resampled coil sensitivity profiles reflecting the movement of slices. Single-shot gradient-echo SMS-EPI scans were performed in phantoms and human subjects for validation. Brain SMS-EPI scans in the presence of motion with PMC and no phase correction for scan plane shift showed noticeable artifacts. These artifacts were visually and quantitatively attenuated when corrections were enabled. Correcting misaligned coil sensitivity maps improved the temporal SNR (tSNR) of time series by 24% (p = 0.0007) for scans with large movements (up to ˜35 mm and 30°). Correcting the receiver phase improved the tSNR of a scan with minimal head movement by 50% from 50 to 75 for a United Kingdom biobank protocol. Reconstruction-induced motion artifacts in single-shot SMS-EPI scans acquired with PMC can be removed by dynamically adjusting the receiver phase of each line across EPI readout trains and updating coil sensitivity profiles during reconstruction. The method may be a valuable tool for SMS-EPI scans in the presence of subject motion.

Race, Ethnicity, and Pharmacogenomic Variation in the United States and the United Kingdom.

The relevance of race and ethnicity to genetics and medicine has long been a matter of debate. An emerging consensus holds that race and ethnicity are social constructs and thus poor proxies for genetic diversity. The goal of this study was to evaluate the relationship between race, ethnicity, and clinically relevant pharmacogenomic variation in cosmopolitan populations. We studied racially and ethnically diverse cohorts of 65,120 participants from the United States All of Us Research Program (All of Us) and 31,396 participants from the United Kingdom Biobank (UKB). Genome-wide patterns of pharmacogenomic variation-6311 drug response-associated variants for All of Us and 5966 variants for UKB-were analyzed with machine learning classifiers to predict participants' self-identified race and ethnicity. Pharmacogenomic variation predicts race/ethnicity with averages of 92.1% accuracy for All of Us and 94.3% accuracy for UKB. Group-specific prediction accuracies range from 99.0% for the White group in UKB to 92.9% for the Hispanic group in All of Us. Prediction accuracies are substantially lower for individuals who identified with more than one group in All of Us (16.7%) or as Mixed in UKB (70.7%). There are numerous individual pharmacogenomic variants with large allele frequency differences between race/ethnicity groups in both cohorts. Frequency differences for toxicity-associated variants predict hundreds of adverse drug reactions per 1000 treated participants for minority groups in All of Us. Our results indicate that race and ethnicity can be used to stratify pharmacogenomic risk in the US and UK populations and should not be discounted when making treatment decisions. We resolve the contradiction between the results reported here and the orthodoxy of race and ethnicity as non-genetic, social constructs by emphasizing the distinction between global and local patterns of human genetic diversity, and we stress the current and future limitations of race and ethnicity as proxies for pharmacogenomic variation.

C-Reactive protein and cognition: Mediation analyses with brain morphology in the UK Biobank

Cognitive impairments and abnormal immune activity are both associated with various clinical disorders. The association between C-Reactive protein (CRP), a marker associated with inflammation, and cognitive performance remains unclear. Further, mechanisms potentially linking CRP to cognition are not yet established. Brain structure may well mediate this relationship: immune processes play crucial roles in shaping and maintaining brain structure, with brain structure and function driving cognition. The United Kingdom Biobank (UKBB) is a large cohort study with extensive assessments, including high-sensitivity serum CRP levels, brain imaging, and various cognitive tasks. With data from 39,200 UKBB participants, we aimed first to determine the relationship between CRP and cognitive performance, and second, to assess metrics of brain morphology as potential mediators in this relationship. Participants were aged 40 to 70 at initial assessment and were mostly Caucasian. After accounting for potential covariates (e.g., age, sex, medical diagnoses, use of selective-serotonin reuptake inhibitors), we found CRP levels to have small, negative associations with fluid intelligence (b = −0.03, 95%CI[-0.05,-0.02], t(14381) = −3.62, pcor = .004), and numeric memory (b = −0.03, 95%CI[-0.05,-0.01], t(14366) = −3.31, pcor = .007). We found no evidence of brain morphology mediating these relationships (all |ab| < 0.001, all pcor > .55). Our findings from this large sample suggest that serum-assessed CRP is of marginal importance for cognitive performance in mid-to-late aged Caucasians; the small effect sizes of statistically significant associations provide context to previous inconsistent results. The seeming lack of involvement of brain morphology suggests that other brain metrics (e.g., connectivity, functional activation) may be more pertinent to this relationship. Future work should also consider CRP levels measured in the central nervous system and/or other cytokines that may better predict cognitive performance in this population.

Association of Rare Variants in ARSA with Parkinson's Disease.

Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA remains unclear. To study rare ARSA variants in PD. To study rare ARSA variants (minor allele frequency < 0.01) in PD, we performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by a meta-analysis. We found evidence for associations between functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each) and in the meta-analysis (P = 0.042). We also found an association between loss-of-function variants and PD in the United Kingdom Biobank cohort (P = 0.005) and in the meta-analysis (P = 0.049). These results should be interpreted with caution as no association survived multiple comparisons correction. Additionally, we describe two families with potential co-segregation of ARSA p.E382K and PD. Rare functional and loss-of-function ARSA variants may be associated with PD. Further replications in large case-control/familial cohorts are required. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Associations between Chronic Kidney Disease and Thinning of Neuroretinal Layers in Multiethnic Asian and White Populations

To evaluate the relationships between chronic kidney disease (CKD) with retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness profiles of eyes in Asian and White populations. Cross-sectional analysis. A total of 5066 Asian participants (1367 Malays, 1772 Indians, and 1927 Chinese) from the Singapore Epidemiology of Eye Diseases Study (SEED) were included, consisting of 9594 eyes for peripapillary RNFL analysis and 8661 eyes for GCIPL analysis. Additionally, 45 064 White participants (87 649 eyes) from the United Kingdom Biobank (UKBB) were included for both macular RNFL analysis and GCIPL analysis. Nonglaucoma participants aged ≥ 40 years with complete data for estimated glomerular filtration rate (eGFR) were included from both SEED and UKBB. In SEED, peripapillary RNFL and GCIPL thickness were measured by Cirrus HD-OCT 4000. In UKBB, macular RNFL and GCIPL were measured by Topcon 3D-OCT 1000 Mark II. Chronic kidney disease was defined as eGFR < 60 ml/min/1.73 m2 in both data sets. To evaluate the associations between kidney function status with RNFL and GCIPL thickness profiles, multivariable linear regression with generalized estimating equation models were performed in SEED and UKBB data sets separately. Average peripapillary and macular RNFL thickness and macular GCIPL thickness. In SEED, after adjusting for age, gender, ethnicity, systolic blood pressure, antihypertensive medication, diabetes, hyperlipidemia, body mass index, smoking status, and intraocular pressure, presence of CKD (β=-1.31; 95% confidence interval [CI],-2.37 to-0.26; P= 0.015) and reduced eGFR (per10ml/min/1.73 m2; β=-0.32; 95% CI,-0.50 to-0.13; P= 0.001) were associated with thinner average peripapillary RNFL. Presence of CKD (β=-1.63; 95% CI,-2.42 to-0.84) and reduced eGFR (per10 ml/min/1.73 m2; β=-0.30; 95% CI,-0.44 to-0.16) were consistently associated with thinner GCIPL in SEED (all P < 0.001). In UKBB, after adjusting for the above-mentioned covariates (except ethnicity), reduced eGFR (per 10 ml/min/1.73 m2; β=-0.06; 95% CI,-0.10 to-0.01; P= 0.008) was associated with thinner macular RNFL and CKD (β=-0.62; 95% CI,-1.16 to-0.08; P= 0.024) was associated with thinner average GCIPL. We consistently observed associations between CKD and thinning of RNFL and GCIPL across Asian and White populations' eyes. These findings further suggest that compromised kidney function is associated with RNFL and GCIPL thinning. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Major depressive disorder plays a vital role in the pathway from gastroesophageal reflux disease to chronic obstructive pulmonary disease: a Mendelian randomization study.

Background: Observational studies have shown a bidirectional association between chronic obstructive pulmonary disease (COPD) and gastroesophageal reflux disease (GERD), but it is not clear whether this association is causal. In our previous study, we found that depression was a hot topic of research in the association between COPD and GERD. Is major depressive disorder (MDD) a mediator of the association between COPD and GERD? Here, we evaluated the causal association between COPD, MDD, and GERD using Mendelian randomization (MR) study. Methods: Based on the FinnGen, United Kingdom Biobank, and Psychiatric Genomics Consortium (PGC) databases, we obtained genome-wide association study (GWAS) summary statistics for the three phenotypes from 315,123 European participants (22,867 GERD cases and 292,256 controls), 462,933 European participants (1,605 COPD cases and 461,328 controls), and 173,005 European participants (59,851 MDD cases and 113,154 controls), respectively. To obtain more instrumental variables to reduce bias, we extracted relevant single-nucleotide polymorphisms (SNPs) for the three phenotypes from published meta-analysis studies. Bidirectional MR and expression quantitative trait loci (eQTL)-MR were performed using the inverse variance weighting method to assess the causal association between GERD, MDD, and COPD. Results: There was no evidence of a causal effect between GERD and COPD in the bidirectional MR analysis [forward MR for GERD on COPD: odds ratios (OR) = 1.001, p = 0.270; reverse MR for COPD on GERD: OR = 1.021, p = 0.303]. The causal effect between GERD and MDD appeared to be bidirectional (forward MR for GERD on MDD: OR = 1.309, p = 0.006; reverse MR for MDD on GERD: OR = 1.530, p < 0.001), while the causal effect between MDD and COPD was unidirectional (forward MR for MDD on COPD: OR = 1.004, p < 0.001; reverse MR for COPD on MDD: OR = 1.002, p = 0.925). MDD mediated the effect of GERD on COPD in a unidirectional manner (OR = 1.001). The results of the eQTL-MR were consistent with those of the bidirectional MR. Conclusion: MDD appears to play a vital role in the effect of GERD on COPD. However, we have no evidence of a direct causal association between GERD and COPD. There is a bidirectional causal association between MDD and GERD, which may accelerate the progression from GERD to COPD.

Variants in JAZF1 are associated with asthma, type 2 diabetes, and height in the United Kingdom biobank population.

Background: Asthma, type 2 diabetes (T2D), and anthropometric measures are correlated complex traits that all have a major genetic component. Objective: To investigate the overlap in genetic variants associated with these complex traits. Methods: Using United Kingdom Biobank data, we performed univariate association analysis, fine-mapping, and mediation analysis to identify and dissect shared genomic regions associated with asthma, T2D, height, weight, body mass index (BMI), and waist circumference (WC). Results: We found several genome-wide significant variants in and around the JAZF1 gene that are associated with asthma, T2D, or height with two of these variants shared by the three phenotypes. We also observed an association in this region with WC when adjusted for BMI. However, there was no association with WC when it was not adjusted for BMI or weight. Additionally, only suggestive associations between variants in this region and BMI were observed. Fine-mapping analyses suggested that within JAZF1 there are non-overlapping regions harboring causal susceptibility variants for asthma, T2D, and height. Mediation analyses supported the conclusion that these are independent associations. Conclusion: Our findings indicate that variants in the JAZF1 are associated with asthma, T2D, and height, but the associated causal variant(s) are different for each of the three phenotypes.