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. Trial registration This study only used secondary data

Predictive value of 8-year blood pressure measures in intracerebral haemorrhage risk over 5 years

Aims The relationships between long-term blood pressure (BP) measures and intracerebral haemorrhage (ICH), as well as their predictive ability on ICH, are unclear. In this study, we aim to investigate the independent associations of multiple BP measures with subsequent 5-year ICH risk, as well as the incremental value of these measures over a single-point BP measurement in ICH risk prediction. Methods and results We included 12 398 participants from the China Kadoorie Biobank (CKB) who completed three surveys every 4–5 years. The following long-term BP measures were calculated: mean, minimum, maximum, standard deviation, coefficient of variation, average real variability, and cumulative BP exposure (cumBP). Cox proportional hazard models were used to examine the associations between these measures and ICH. The potential incremental value of these measures in ICH risk prediction was assessed using Harrell’s C statistics, continuous net reclassification improvement (cNRI), and relative integrated discrimination improvement (rIDI). The hazard ratios (95% confidence intervals) of incident ICH associated with per standard deviation increase in cumulative systolic BP and cumulative diastolic BP were 1.62 (1.25–2.10) and 1.59 (1.23–2.07), respectively. When cumBP was added to the conventional 5-year ICH risk prediction model, the C-statistic change was 0.009 (−0.001, 0.019), the cNRI was 0.267 (0.070–0.464), and the rIDI was 18.2% (5.8–30.7%). Further subgroup analyses revealed a consistent increase in cNRI and rIDI in men, rural residents, and participants without diabetes. Other long-term BP measures showed no statistically significant associations with incident ICH and generally did not improve model performance. Conclusion The nearly 10-year cumBP was positively associated with an increased 5-year risk of ICH and could significantly improve risk reclassification for the ICH risk prediction model that included single-point BP measurement

The supernova rate and delay time distribution in the Magellanic Clouds

We use the supernova remnants (SNRs) in the Magellanic Clouds (MCs) as a supernova (SN) survey, "conducted" over tens of kyr, from which we derive the current SN rate, and the SN delay time distribution (DTD), i.e., the SN rate vs. time that would follow a hypothetical brief burst of a star formation. In Badenes, Maoz, & Draine (2010) we have compiled a list of 77 SNRs in the MCS, and argued it is a fairly complete record of the SNRs in the Sedov phase of their expansions. We recover the DTD by comparing the numbers of SNRs observed in small individual "cells" in these galaxies to the star-formation histories of each cell, as calculated from resolved stellar populations by Harris & Zaritsky. The visibility times of SNRs are the Sedov-phase lifetimes, which depend on the local ambient densities. The local densities are estimated from HI emission, from an inverse Schmidt law based on either Halpha flux or on the resolved star-formation rate, and from combinations of these tracers. In the DTD, we detect "prompt" type-Ia SNe (that explode within 330 Myr of star formation) at >99% confidence level (c.l.). The best fit for the number of prompt SNe-Ia per stellar mass formed is (2.7-11.0) x 10^{-3} /Msun, depending on the density tracer used. The 95% c.l. range for a "delayed" SN Ia component (from 330 Myr to a Hubble time) is < 1.6 x 10^{-13} SN/yr/Msun, consistent with rate measurements in old populations. The current total (core-collapse+Ia) SN rate in the MCs is 2.5-4.6 SNe per millenium (68% c.l.+systematics), or 1.7-3.1 SNuM [SNe/100 yr/10^{10}Msun], in agreement with the historical record and with rates measured in other dwarf irregulars. Conversely, assuming the SNRs are in free expansion, rather than in their Sedov phase, would impose on the SNRs a maximum age of 6 kyr, and would imply a MC SN rate per unit mass that is 5 times higher than in any type of galaxy.Comment: MNRAS, in pres

Conventional and genetic associations of adiposity with 1463 proteins in relatively lean Chinese adults

Adiposity is associated with multiple diseases and traits, but little is known about the causal relevance and mechanisms underlying these associations. Large-scale proteomic profiling, especially when integrated with genetic data, can clarify mechanisms linking adiposity with disease outcomes. We examined the associations of adiposity with plasma levels of 1463 proteins in 3977 Chinese adults, using measured and genetically-instrumented BMI. We further used two-sample bi-directional MR analyses to assess if certain proteins influenced adiposity, along with other (e.g. enrichment) analyses to clarify possible mechanisms underlying the observed associations. Overall, the mean (SD) baseline BMI was 23.9 (3.3) kg/m2, with only 6% being obese (i.e. BMI ≥ 30 kg/m2). Measured and genetically-instrumented BMI was significantly associated at FDR  90%) in Europeans of UKB (mean BMI 27.4 kg/m2). Enrichment analyses of the top > 50 BMI-associated proteins demonstrated their involvement in atherosclerosis, lipid metabolism, tumour progression and inflammation. Two-sample bi-directional MR analyses using cis-pQTLs identified in CKB GWAS found eight proteins (ITIH3, LRP11, SCAMP3, NUDT5, OGN, EFEMP1, TXNDC15, PRDX6) significantly affect levels of BMI, with NUDT5 also showing bi-directional association. The findings among relatively lean Chinese adults identified novel pathways by which adiposity may increase disease risks and novel potential targets for treatment of obesity and obesity-related diseases

Causal relevance of different blood pressure traits on risk of cardiovascular diseases: GWAS and Mendelian randomisation in 100,000 Chinese adults

Elevated blood pressure (BP) is major risk factor for cardiovascular diseases (CVD). Genome-wide association studies (GWAS) conducted predominantly in populations of European ancestry have identified >2,000 BP-associated loci, but other ancestries have been less well-studied. We conducted GWAS of systolic, diastolic, pulse, and mean arterial BP in 100,453 Chinese adults. We identified 128 non-overlapping loci associated with one or more BP traits, including 74 newly-reported associations. Despite strong genetic correlations between populations, we identified appreciably higher heritability and larger variant effect sizes in Chinese compared with European or Japanese ancestry populations. Using instruments derived from these GWAS, multivariable Mendelian randomisation demonstrated that BP traits contribute differently to the causal associations of BP with CVD. In particular, only pulse pressure was independently causally associated with carotid plaque. These findings reinforce the need for studies in diverse populations to understand the genetic determinants of BP traits and their roles in disease risk

Proteomic analyses in diverse populations improved risk prediction and identified new drug targets for type 2 diabetes

Objective: Integrated analyses of plasma proteomics and genetic data in prospective studies can help assess the causal relevance of proteins, improve risk prediction and discover novel protein drug targets for T2D. Research Design and Methods: We measured plasma levels of 2923 proteins using OLINK Explore among ~2000 randomly selected participants from CKB without prior diabetes at baseline. Cox regression assessed associations of individual protein with incident T2D (n=92 cases). Proteomic-based risk models were developed with discrimination, calibration, reclassification assessed using AUC, calibration plots and NRI, respectively. Two-sample MR analyses using cis-pQTLs identified in GWAS of CKB and UKB for specific proteins were conducted to assess their causal relevance for T2D, along with colocalization analyses to examine shared causal variants between proteins and T2D. Results: Overall 33 proteins were significantly associated (FDR0.6) of shared genetic variants of LPL and PON3 with T2D. Conclusion: Proteomic analyses in Chinese adults identified novel associations of multiple proteins with T2D with strong genetic evidence supporting their causal relevance and potential as novel drug targets for prevention and treatment of T2D

Genotyping and population characteristics of the China Kadoorie Biobank.

The China Kadoorie Biobank (CKB) is a population-based prospective cohort of >512,000 adults recruited from 2004 to 2008 from 10 geographically diverse regions across China. Detailed data from questionnaires and physical measurements were collected at baseline, with additional measurements at three resurveys involving ∼5% of surviving participants. Analyses of genome-wide genotyping, for >100,000 participants using custom-designed Axiom arrays, reveal extensive relatedness, recent consanguinity, and signatures reflecting large-scale population movements from recent Chinese history. Systematic genome-wide association studies of incident disease, captured through electronic linkage to death and disease registries and to the national health insurance system, replicate established disease loci and identify 14 novel disease associations. Together with studies of candidate drug targets and disease risk factors and contributions to international genetics consortia, these demonstrate the breadth, depth, and quality of the CKB data. Ongoing high-throughput omics assays of collected biosamples and planned whole-genome sequencing will further enhance the scientific value of this biobank

Evidence for Type Ia Supernova Diversity from Ultraviolet Observations with the Hubble Space Telescope

We present ultraviolet (UV) spectroscopy and photometry of four Type Ia supernovae (SNe 2004dt, 2004ef, 2005M, and 2005cf) obtained with the UV prism of the Advanced Camera for Surveys on the Hubble Space Telescope. This dataset provides unique spectral time series down to 2000 Angstrom. Significant diversity is seen in the near maximum-light spectra (~ 2000--3500 Angstrom) for this small sample. The corresponding photometric data, together with archival data from Swift Ultraviolet/Optical Telescope observations, provide further evidence of increased dispersion in the UV emission with respect to the optical. The peak luminosities measured in uvw1/F250W are found to correlate with the B-band light-curve shape parameter dm15(B), but with much larger scatter relative to the correlation in the broad-band B band (e.g., ~0.4 mag versus ~0.2 mag for those with 0.8 < dm15 < 1.7 mag). SN 2004dt is found as an outlier of this correlation (at > 3 sigma), being brighter than normal SNe Ia such as SN 2005cf by ~0.9 mag and ~2.0 mag in the uvw1/F250W and uvm2/F220W filters, respectively. We show that different progenitor metallicity or line-expansion velocities alone cannot explain such a large discrepancy. Viewing-angle effects, such as due to an asymmetric explosion, may have a significant influence on the flux emitted in the UV region. Detailed modeling is needed to disentangle and quantify the above effects.Comment: 17 pages, 13 figures, accepted by Ap

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele