Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signalling and brain ageing-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and ADHD. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

Multi-Omics Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations.

The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10-12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10-10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10-4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases.

Reclaiming mendelian randomization from the deluge of papers and misleading findings.

Mendelian randomization (MR) is a powerful epidemiological method for causal inference. However, its recent surge in popularity has brought two concerning trends. First, the public availability of summary results from genome-wide association studies has led to an explosion of low-quality two-sample mendelian randomization (2SMR) studies. These studies add minimal - if any - value and overwhelm reviewers and journals. Second, the availability of large datasets with individual-level genotype data, like UK Biobank, has spurred the development and use of novel MR methods. However, some methods are being applied without proper testing, leading to misleading results, as exemplified by recent spurious findings that are being retracted and/or corrected relating to vitamin D. What can editors and peer reviewers do to handle the deluge of 2SMR studies and the premature application of highly complex MR methods? We advise editors to simply reject papers that only report 2SMR findings, with no additional supporting evidence. For reviewers receiving such papers, we provide a template for rejection. In addition, reviewers should demand rigorous testing of novel methods, including through the use of positive and negative controls before they are applied. Rejecting non-contributory 2SMR papers and imposing intensive scrutiny to novel methods is crucial if the scientific community is to reclaim MR.

Bidirectional Mendelian randomization highlights causal relationships between circulating INHBC and multiple cardiometabolic diseases and traits.

Human genetic and transgenic mouse studies have highlighted a potential liver-adipose tissue endocrine axis, involving activin C (Act-C) and/or Act-E and ALK7, influencing fat distribution and systemic metabolism. We investigated the bidirectional effects between circulating INHBC, which homodimerizes into Act-C, and adiposity traits, insulin resistance, inflammation, and cardiometabolic disease risk. Additionally, we examined if Act-C is an ALK7 ligand in human adipocytes. We used Mendelian randomization and in vitro studies in immortalized human abdominal and gluteal adipocytes. Circulating INHBC was causally linked to reduced lower-body fat, dyslipidaemia, and increased risks of coronary artery disease (CAD) and non-alcoholic fatty liver disease (NAFLD). Conversely, upper-body fat distribution, obesity, hypertriglyceridemia, subclinical inflammation, and type 2 diabetes positively impacted plasma INHBC levels. Mechanistically, an atherogenic lipid profile may partly explain the INHBC-CAD link, while inflammation and hypertriglyceridemia may partly explain how adiposity traits affect circulating INHBC. Phenome-wide Mendelian randomization showed weak causal relationships between higher plasma INHBC and impaired kidney function and higher gout risk. In human adipocytes, recombinant Act-C activated SMAD2/3 signaling via ALK7 and suppressed lipolysis. In summary, INHBC influences systemic metabolism by activating ALK7 in adipose tissue and may serve as a drug target for atherogenic dyslipidemia, CAD, and NAFLD.

Educational attainment and mental health conditions: a within-sibship Mendelian randomization study.

Importance: Observational studies have demonstrated consistent protective effects of higher educational attainment (EA) on the risk of suffering mental health conditions (MHC). Determining whether these beneficial effects are causal is challenging given the potential role of dynastic effects and demographic factors (assortative mating and population structure) in this association. Objective: To evaluate to what extent the relationship between EA and various MHC is independent from dynastic effects and demographic factors. Design: Within-sibship Mendelian randomization (MR) study. Setting: One-sample MR analyses included participants' data from the Trøndelag Health Study (HUNT, Norway) and UK Biobank (United Kingdom). For two-sample MR analyses we used summary statistics from publicly available genome-wide-association-studies. Participants: 61 880 siblings (27 507 sibships). Exposure: Years of education. Main outcomes: Scores for symptoms of anxiety, depression and neuroticism using the Hospital Anxiety Depression Scale (HADS), the 7-item Generalized Anxiety Disorder Scale (GAD-7), the 9-item Patient Health Questionnaire (PHQ-9), and the Eysenck Personality Questionnaire, as well as self-reported consumption of psychotropic medication. Results: One standard deviation (SD) unit increase in years of education was associated with a lower symptom score of anxiety (-0.20 SD [95%CI: -0.26, -0.14]), depression (-0.11 SD [-0.43, 0.22]), neuroticism (-0.30 SD [-0.53, -0.06]), and lower odds of psychotropic medication consumption (OR: 0.60 [0.52, 0.69]). Estimates from the within-sibship MR analyses showed some attenuation, which however were suggestive of a causal association (anxiety: -0.17 SD [-0.33, -0.00]; depression: -0.18 SD [-1.26, 0.89]; neuroticism: -0.29 SD [-0.43, -0.15]); psychotropic medication consumption: OR, 0.52 [0.34, 0.82]). Conclusions and Relevance: Associations between EA and MHC in adulthood, although to some extend explained by dynastic effects and demographic factors, overall remain robust, indicative of a causal effect. However, larger studies are warranted to improve statistical power and further validate our conclusions.

The effect of SGLT2 inhibition on prostate cancer: Mendelian randomization and observational analysis using electronic healthcare and cohort data.

We evaluated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on prostate cancer by evidence triangulation. Using Mendelian randomization, we found that genetically proxied SGLT2 inhibition reduced the risk of overall (odds ratio = 0.56, 95% confidence interval [CI] = 0.38 to 0.82; 79,148 prostate cancer cases and 61,106 controls), advanced, and early-onset prostate cancer. Using electronic healthcare data (nSGLT2i = 24,155; nDPP4i = 24,155), we found that the use of SGLT2 inhibitors was associated with a 23% reduced risk of prostate cancer (hazard ratio = 0.77, 95% CI = 0.61 to 0.99) in men with diabetes. Using data from two prospective cohorts (n4C = 57,779; nUK_Biobank = 165,430), we found little evidence to support the association of HbA1c with prostate cancer, implying a non-glycemic effect of SGLT2 inhibition on prostate cancer. In summary, this study provides multiple layers of evidence to support the beneficial effect of SGLT2 inhibition on reducing prostate cancer risk. Future trials are warranted to investigate whether SGLT2 inhibitors can be recommended for prostate cancer prevention.

Parental education and children's depression, anxiety, and ADHD traits, a within-family study in MoBa.

Children born to parents with fewer years of education are more likely to have depression, anxiety, and attention-deficit hyperactivity disorder (ADHD), but it is unclear to what extent these associations are causal. We estimated the effect of parents' educational attainment on children's depressive, anxiety, and ADHD traits at age 8 years, in a sample of 40,879 Norwegian children born in 1998-2009 and their parents. We used within-family Mendelian randomization, which employs genetic variants as instrumental variables, and controlled for direct genetic effects by adjusting for children's polygenic indexes. We found little evidence that mothers' or fathers' educational attainment independently affected children's depressive, anxiety, or ADHD traits. However, children's own polygenic scores for educational attainment were independently and negatively associated with these traits. Results suggest that differences in these traits according to parents' education may reflect direct genetic effects more than genetic nurture. Consequences of social disadvantage for children's mental health may however be more visible in samples with more socioeconomic variation, or contexts with larger socioeconomic disparities than present-day Norway. Further research is required in populations with more educational and economic inequality and in other age groups.

Epigenetic Aging and Racialized, Economic, and Environmental Injustice: NIMHD Social Epigenomics Program.

Importance: Epigenetic age acceleration is associated with exposure to social and economic adversity and may increase the risk of premature morbidity and mortality. However, no studies have included measures of structural racism, and few have compared estimates within or across the first and second generation of epigenetic clocks. Objective: To determine whether epigenetic age acceleration is positively associated with exposures to diverse measures of racialized, economic, and environmental injustice measured at different levels and time periods. Design, Setting, and Participants: This cross-sectional study used data from the My Body My Story (MBMS) study between August 8, 2008, and December 31, 2010, and examination 5 of the Multi-Ethnic Atherosclerosis Study (MESA) from April 1, 2010, to February 29, 2012. In the MBMS, DNA extraction was performed in 2021; linkage of structural measures to the MBMS and MESA, in 2022. US-born individuals were randomly selected from 4 community health centers in Boston, Massachusetts (MBMS), and 4 field sites in Baltimore, Maryland; Forsyth County, North Carolina; New York City, New York; and St Paul, Minnesota (MESA). Data were analyzed from November 13, 2021, to August 31, 2023. Main Outcomes and Measures: Ten epigenetic clocks (6 first-generation and 4 second-generation), computed using DNA methylation data (DNAm) from blood spots (MBMS) and purified monocytes (MESA). Results: The US-born study population included 293 MBMS participants (109 men [37.2%], 184 women [62.8%]; mean [SD] age, 49.0 [8.0] years) with 224 Black non-Hispanic and 69 White non-Hispanic participants and 975 MESA participants (492 men [50.5%], 483 women [49.5%]; mean [SD] age, 70.0 [9.3] years) with 229 Black non-Hispanic, 191 Hispanic, and 555 White non-Hispanic participants. Of these, 140 (11.0%) exhibited accelerated aging for all 5 clocks whose estimates are interpretable on the age (years) scale. Among Black non-Hispanic MBMS participants, epigenetic age acceleration was associated with being born in a Jim Crow state by 0.14 (95% CI, 0.003-0.27) SDs and with birth state conservatism by 0.06 (95% CI, 0.01-0.12) SDs, pooling across all clocks. Low parental educational level was associated with epigenetic age acceleration, pooling across all clocks, for both Black non-Hispanic (0.24 [95% CI, 0.08-0.39] SDs) and White non-Hispanic (0.27 [95% CI, 0.03-0.51] SDs) MBMS participants. Adult impoverishment was positively associated with the pooled second-generation clocks among the MESA participants (Black non-Hispanic, 0.06 [95% CI, 0.01-0.12] SDs; Hispanic, 0.07 [95% CI, 0.01-0.14] SDs; White non-Hispanic, 0.05 [95% CI, 0.01-0.08] SDs). Conclusions and Relevance: The findings of this cross-sectional study of MBMS and MESA participants suggest that epigenetic age acceleration was associated with racialized and economic injustice, potentially contributing to well-documented inequities in premature mortality. Future research should test the hypothesis that epigenetic accelerated aging may be one of the biological mechanisms underlying the well-documented elevated risk of premature morbidity and mortality among social groups subjected to racialized and economic injustice.

Novel genomic variants related to visceral adiposity index (VAI) and body adiposity index (BAI) in Indian sib-pairs.

BACKGROUND: Obesity is among the leading public health threats globally. Over the last few years, visceral adiposity index (VAI), and body adiposity index (BAI), derived from anthropometric, and biochemical measures, have gained importance as a measure of obesity. However, unlike other common indices like body mass index, and waist circumference, the genetic predisposition of VAI, and BAI under-examined. METHODS: 2265 sib-pairs from Indian Migration Study were used for examining the association of genetic variants from the Cardio-Metabochip array with VAI, and BAI. Mixed linear regression models were run, and all inferences were based on the within-sib component of the Fulker's association models. Gene-environment/lifestyle interaction analyses were also undertaken. RESULTS: rs6659428 at LOC400796 | SEC16B (ß = 0.26, SE = 0.05), and rs7611535 at DRD3 | LOC645180 (ß = 0.18, SE = 0.04) were associated with VAI at suggestive significance value of <8.21 × 10-6. For BAI, rs73300702 at JAZF1-AS1 (ß = 0.27, SE = 0.06), was the top hit at p value < 8.21 × 10-6. Further, rs6659428 showed marginal effect modification with rural/urban location (ß = 0.26, SE = 0.13, p value = 0.047), and rs73300702 with physical activity (ß = -0.29,SE = 0.14, p value = 0.034). CONCLUSION: We report three novel genetic loci for VAI, and BAI in Indians that are important indicators of adiposity. These findings need to be replicated and validated with larger samples from different ethnicities. Further, functional studies for understanding the biological mechanisms of these adiposity indices need to be undertaken to understand the underlying pathophysiology.

Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study.

Background: Low-grade systemic inflammation is implicated in the pathogenesis of various neuropsychiatric conditions affecting mood and cognition. While much of the evidence concerns depression, large-scale population studies of anxiety, affect, and cognitive function are scarce. Importantly, causality remains unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognitive performance in the Lifelines Cohort; and whether associations are likely to be causal. Methods: Using data from up to 55,098 (59% female) individuals from the Dutch Lifelines cohort, we tested the cross-sectional and longitudinal associations of C-reactive protein (CRP) with (i) depressive and anxiety disorders; (ii) positive and negative affect scores, and (iii) five cognitive measures assessing attention, psychomotor speed, episodic memory, and executive functioning (figural fluency and working memory). Additionally, we examined the association between inflammatory marker GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (Nmax=57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (Nmax=23,268). In genetic analyses, all GRSs and outcomes were z-transformed. Results: In non-genetic analyses, higher CRP was associated with diagnosis of any depressive disorder, lower positive and higher negative affect scores, and worse performance on tests of figural fluency, attention, and psychomotor speed after adjusting for potential confounders, although the magnitude of these associations was small. In genetic analyses, CRPGRS was associated with any anxiety disorder (ß=0.002, p=0.037, N=57,047) whereas GlycAGRS was associated with major depressive disorder (ß=0.001, p=0.036; N=57,047). Both CRPGRS (ß=0.006, p=0.035, N=57,946) and GlycAGRS (ß=0.006, p=0.049; N=57,946) were associated with higher negative affect score. Inflammatory marker GRSs were not associated with cognitive performance, except sIL-6RGRS which was associated with poorer memory performance (ß=-0.009, p=0.018, N=36,783). Further examination of the CRP-anxiety association using MR provided some weak evidence of causality (ß=0.12; p=0.054). Conclusions: Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. Genetic analyses suggest that IL-6 signaling could be relevant for memory, and that the association between CRP and anxiety disorders could be causal. These results suggest that dysregulated immune physiology may impact a broad range of trans-diagnostic affective symptoms. However, given the small effect sizes and multiple tests conducted, future studies are required to investigate whether effects are moderated by sub-groups and whether these findings replicate in other cohorts.

Genomic insights into the comorbidity between type 2 diabetes and schizophrenia.

Multimorbidity represents an increasingly important public health challenge with far-reaching implications for health management and policy. Mental health and metabolic diseases have a well-established epidemiological association. In this study, we investigate the genetic intersection between type 2 diabetes and schizophrenia. We use Mendelian randomization to examine potential causal relationships between the two conditions and related endophenotypes. We report no compelling evidence that type 2 diabetes genetic liability potentially causally influences schizophrenia risk and vice versa. Our findings show that increased body mass index (BMI) has a protective effect against schizophrenia, in contrast to the well-known risk-increasing effect of BMI on type 2 diabetes risk. We identify evidence of colocalization of association signals for these two conditions at 11 genomic loci, six of which have opposing directions of effect for type 2 diabetes and schizophrenia. To elucidate these colocalizing signals, we integrate multi-omics data from bulk and single-cell gene expression studies, along with functional information. We identify putative effector genes and find that they are enriched for homeostasis and lipid-related pathways. We also highlight drug repurposing opportunities including N-methyl-D-aspartate (NMDA) receptor antagonists. Our findings provide insights into shared biological mechanisms for type 2 diabetes and schizophrenia, highlighting common factors that influence the risk of the two conditions in opposite directions and shedding light on the complex nature of this comorbidity.

Protein identification for stroke progression via Mendelian Randomization in Million Veteran Program and UK Biobank.

Background: Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke. Methods: We performed genome-wide association studies (GWAS) for subsequent major adverse cardiovascular events (MACE) (Ncases=51,929, Ncntrl=39,980) and subsequent arterial ischemic stroke (AIS) Ncases=45,120, Ncntrl=46,789) after first incident stroke within the Million Veteran Program and UK Biobank. We then used genetic variants associated with proteins (pQTLs) to determine the effect of 1,463 plasma protein abundances on subsequent MACE using Mendelian randomization (MR). Results: Two variants were significantly associated with subsequent cardiovascular events: rs76472767 (OR=0.75, 95% CI = 0.64-0.85, p= 3.69×10-08) with subsequent AIS and rs13294166 (OR=1.52, 95% CI = 1.37-1.67, p=3.77×10-08) with subsequent MACE. Using MR, we identified 2 proteins with an effect on subsequent MACE after a stroke: CCL27 (effect OR= 0.77, 95% CI = 0.66-0.88, adj. p=0.05), and TNFRSF14 (effect OR=1.42, 95% CI = 1.24-1.60, adj. p=0.006). These proteins are not associated with incident AIS and are implicated to have a role in inflammation. Conclusions: We found evidence that two proteins with little effect on incident stroke appear to influence subsequent MACE after incident AIS. These associations suggest that inflammation is a contributing factor to subsequent MACE outcomes after incident AIS and highlights potential novel targets.

An epigenome-wide analysis of DNA methylation, racialized and economic inequities, and air pollution.

Importance: DNA methylation (DNAm) provides a plausible mechanism by which adverse exposures become embodied and contribute to health inequities, due to its role in genome regulation and responsiveness to social and biophysical exposures tied to societal context. However, scant epigenome-wide association studies (EWAS) have included structural and lifecourse measures of exposure, especially in relation to structural discrimination. Objective: Our study tests the hypothesis that DNAm is a mechanism by which racial discrimination, economic adversity, and air pollution become biologically embodied. Design: A series of cross-sectional EWAS, conducted in My Body My Story (MBMS, biological specimens collected 2008-2010, DNAm assayed in 2021); and the Multi Ethnic Study of Atherosclerosis (MESA; biological specimens collected 2010-2012, DNAm assayed in 2012-2013); using new georeferenced social exposure data for both studies (generated in 2022). Setting: MBMS was recruited from four community health centers in Boston; MESA was recruited from four field sites in: Baltimore, MD; Forsyth County, NC; New York City, NY; and St. Paul, MN. Participants: Two population-based samples of US-born Black non-Hispanic (Black NH), white non-Hispanic (white NH), and Hispanic individuals (MBMS; n=224 Black NH and 69 white NH) and (MESA; n=229 Black NH, n=555 white NH and n=191 Hispanic). Exposures: Eight social exposures encompassing racial discrimination, economic adversity, and air pollution. Main outcome: Genome-wide changes in DNAm, as measured using the Illumina EPIC BeadChip (MBMS; using frozen blood spots) and Illumina 450k BeadChip (MESA; using purified monocytes). Our hypothesis was formulated after data collection. Results: We observed the strongest associations with traffic-related air pollution (measured via black carbon and nitrogen oxides exposure), with evidence from both studies suggesting that air pollution exposure may induce epigenetic changes related to inflammatory processes. We also found suggestive associations of DNAm variation with measures of structural racial discrimination (e.g., for Black NH participants, born in a Jim Crow state; adult exposure to racialized economic residential segregation) situated in genes with plausible links to effects on health. Conclusions and Relevance: Overall, this work suggests that DNAm is a biological mechanism through which structural racism and air pollution become embodied and may lead to health inequities.

Childhood socioeconomic position and sex-specific trajectories of metabolic traits across early life: prospective cohort study.

BACKGROUND: Socioeconomic inequalities in cardiovascular disease risk begin early in life and are more pronounced in females than males later in life. Causal atherogenic traits explaining this are not well understood. We explored sex-specific associations between childhood socioeconomic position (SEP) and molecular measures of systemic metabolism across early life. METHODS: Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort in southwest England. Pregnant women with an expected delivery date between 1991 and 1992 were invited to participate. Maternal education was the primary indicator of SEP. Concentrations of 148 metabolic traits from targeted metabolomics (nuclear magnetic resonance spectroscopy) from research clinics at ages 7, 15, 18 and 25 years were analysed. The sex-specific slope index of inequality (SII) in trajectories of metabolic traits was estimated using multilevel models. FINDINGS: Total number of participants included was 6537 (12,543 repeated measures). Lower maternal education was associated with more adverse levels of several atherogenic lipids and key metabolic traits among females at age 7 years, but not males. For instance, SII for very small very-low-density lipoprotein (VLDL) concentrations was 0.16SD (95% CI: 0.01, 0.30) among females and -0.02SD (95% CI: -0.16, 0.13) among males. Between 7 and 25 years, inequalities widened among females and emerged among males particularly for VLDL particle concentrations, apolipoprotein-B concentrations, and inflammatory glycoprotein acetyls. For instance, at 25 years, SII for very small VLDL concentrations was 0.36SD (95% CI: 0.20, 0.52) and 0.22SD (95% CI: 0.04, 0.40) among females and males respectively. INTERPRETATION: Prevention of socioeconomic inequalities in cardiovascular disease risk requires a life course approach beginning at the earliest opportunity, especially among females. FUNDING: The UK Medical Research Council and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). KON is supported by a Health Research Board (HRB) of Ireland Investigator Led Award (ILP-PHR-2022-008). JB, GDS and KT work in a unit funded by the UK MRC (MC_UU_00011/1 and MC UU 00011/3) and the University of Bristol. OR is supported by a UKRI Future Leaders Fellowship (MR/S03532X/1). These funding sources had no role in the design and conduct of this study. This publication is the work of the authors and KON will serve as guarantor for the contents of this paper.

Genetic influences on alcohol flushing in East Asian populations.

BACKGROUND: Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited. METHODS: We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake. RESULTS: We identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke). CONCLUSION: This study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.

Genomic insights into the comorbidity between type 2 diabetes and schizophrenia.

Multimorbidity represents an increasingly important public health challenge with far-reaching implications for health management and policy. Mental health and metabolic diseases have a well-established epidemiological association. In this study, we investigate the genetic intersection between type 2 diabetes and schizophrenia. We use Mendelian randomization to examine potential causal relationships between the two conditions and related endophenotypes. We report no compelling evidence that type 2 diabetes genetic liability potentially causally influences schizophrenia risk and vice versa. Our findings show that increased body mass index (BMI) has a protective effect against schizophrenia, in contrast to the well-known risk-increasing effect of BMI on type 2 diabetes risk. We identify evidence of colocalization of association signals for these two conditions at 11 genomic loci, six of which have opposing directions of effect for type 2 diabetes and schizophrenia. To elucidate these colocalizing signals, we integrate multi-omics data from bulk and single-cell gene expression studies, along with functional information. We identify high-confidence effector genes and find that they are enriched for homeostasis and lipid-related pathways. We also highlight drug repurposing opportunities including N-methyl-D-aspartate (NMDA) receptor antagonists. Our findings provide insights into shared biological mechanisms for type 2 diabetes and schizophrenia, highlighting common factors that influence the risk of the two conditions in opposite directions and shedding light on the complex nature of this comorbidity.

Low levels of small HDL particles predict but do not influence risk of sepsis.

BACKGROUND: Low levels of high-density lipoprotein (HDL) cholesterol have been associated with higher rates and severity of infection. Alterations in inflammatory mediators and infection are associated with alterations in HDL cholesterol. It is unknown whether the association between HDL and infection is present for all particle sizes, and whether the observed associations are confounded by IL-6 signalling. METHODS: In the UK Biobank, ~ 270,000 individuals have data on HDL subclasses derived from nuclear magnetic resonance analysis. We estimated the association of particle count of total HDL and HDL subclasses (small, medium, large, and extra-large HDL) with sepsis, sepsis-related death, and critical care admission in a Cox regression model. We subsequently utilised genetic data from UK Biobank and FinnGen to perform Mendelian randomisation (MR) of each HDL subclass and sepsis to test for a causal relationship. Finally, we explored the role of IL-6 signalling as a potential causal driver of changes in HDL subclasses. RESULTS: In observational analyses, higher particle count of small HDL was associated with protection from sepsis (Hazard ratio, HR 0.80; 95% CI 0.74-0.86, p = 4 × 10-9 comparing Quartile 4, highest quartile of HDL to Quartile 1, lowest quartile of HDL), sepsis-related death (HR 0.80; 95% CI 0.74-0.86, p = 2 × 10-4), and critical care admission with sepsis (HR 0.72 95% CI 0.60-0.85, p = 2 × 10-4). Parallel associations with other HDL subclasses were likely driven by changes in the small HDL compartment. MR analyses did not strongly support causality of small HDL particle count on sepsis incidence (Odds ratio, OR 0.98; 95% CI 0.89-1.07, p = 0.6) or death (OR 0.94, 95% CI 0.75-1.17, p = 0.56), although the estimate on critical care admission with sepsis supported protection (OR 0.73, 95% CI 0.57-0.95, p = 0.02). Bidirectional MR analyses suggested that increased IL-6 signalling was associated with reductions in both small (beta on small HDL particle count - 0.16, 95% CI - 0.10 to - 0.21 per natural log change in SD-scaled CRP, p = 9 × 10-8).and total HDL particle count (beta - 0.13, 95% CI - 0.09 to - 0.17, p = 7 × 10-10), but that the reverse effect of HDL on IL-6 signalling was largely null. CONCLUSIONS: Low number of small HDL particles are associated with increased hazard of sepsis, sepsis-related death, and sepsis-related critical care admission. However, genetic analyses did not strongly support this as causal. Instead, we demonstrate that increased IL-6 signalling, which is known to alter infection risk, could confound associations with reduced HDL particle count, and suggest this may explain part of the observed association between (small) HDL particle count and sepsis.

Time-sensitive testing pressures and COVID-19 outcomes: are socioeconomic inequalities over the first year of the pandemic explained by selection bias?

BACKGROUND: There are many ways in which selection bias might impact COVID-19 research. Here we focus on selection for receiving a polymerase-chain-reaction (PCR) SARS-CoV-2 test and how known changes to selection pressures over time may bias research into COVID-19 infection. METHODS: Using UK Biobank (N = 420,231; 55% female; mean age = 66.8 [SD = 8·11]) we estimate the association between socio-economic position (SEP) and (i) being tested for SARS-CoV-2 infection versus not being tested (ii) testing positive for SARS-CoV-2 infection versus testing negative and (iii) testing negative for SARS-CoV-2 infection versus not being tested. We construct four distinct time-periods between March 2020 and March 2021, representing distinct periods of testing pressures and lockdown restrictions and specify both time-stratified and combined models for each outcome. We explore potential selection bias by examining associations with positive and negative control exposures. RESULTS: The association between more disadvantaged SEP and receiving a SARS-CoV-2 test attenuated over time. Compared to individuals with a degree, individuals whose highest educational qualification was a GCSE or equivalent had an OR of 1·27 (95% CI: 1·18 to 1·37) in March-May 2020 and 1·13 (95% CI: 1.·10 to 1·16) in January-March 2021. The magnitude of the association between educational attainment and testing positive for SARS-CoV-2 infection increased over the same period. For the equivalent comparison, the OR for testing positive increased from 1·25 (95% CI: 1·04 to 1·47), to 1·69 (95% CI: 1·55 to 1·83). We found little evidence of an association between control exposures, and any considered outcome. CONCLUSIONS: The association between SEP and SARS-CoV-2 testing changed over time, highlighting the potential of time-specific selection pressures to bias analyses of COVID-19. Positive and negative control analyses suggest that changes in the association between SEP and SARS-CoV-2 infection over time likely reflect true increases in socioeconomic inequalities.