Understanding the impacts of extreme drought on forest productivity requires a comprehensive assessment of tree and forest resilience. However, current approaches to quantifying resilience limit our ...understanding of forest response dynamics, recovery trajectories and drought legacies by constraining the temporal scale and resolution of assessment.
We compared individual tree growth histories with growth forecasted using dynamic regression at an annual resolution, allowing drought impact and individual tree and stand level recovery dynamics to be assessed relative to a scenario where no drought occurred. The novel application of this approach allowed us to quantify the cumulative impact of drought legacy on radial growth at multiple stem heights at different stand densities.
We show that the choice of pre‐ and post‐drought periods over which resilience is assessed can lead to systematic bias in both estimates and interpretations of resilience indices. In contrast, measuring growth resilience annually revealed clear nonlinearities in tree and stand recovery trajectories. Furthermore, we demonstrate that the influence of pre‐drought attributes such as tree size, growth rates and stand densities on growth resilience were only detectable at certain stages of recovery. Importantly, we show that the legacy of drought on tree growth can become positive for some individuals, extending up to 9 years after the event such that post‐recovery growth can result in the reclamation of some lost tree and stand basal area.
Synthesis. We demonstrate the importance of increasing the temporal scale and resolution of forest resilience assessment in order to understand both patterns and drivers of drought recovery. We highlight the shortcomings of collapsing growth response into a single average value and show how drought legacy can persist into a post‐recovery phase, even positively impacting the growth of some trees. If unaccounted for, this post‐recovery growth phase can lead to an underestimation of resilience and an overestimation of above‐ground losses in productivity, highlighting the importance of considering longer‐term drought legacies and compensatory growth on basal area.
We demonstrate the importance of increasing the temporal scale and resolution of forest resilience assessment to understand patterns in drought recovery by showing how drought legacy can persist into a post‐recovery phase in the form of compensatory growth, positively impacting the growth of some trees. If unaccounted for, this post‐recovery growth can lead to an underestimation of resilience and an overestimation of above ground losses in productivity.
Alcohol consumption and smoking, 2 major risk factors for cardiovascular disease (CVD), often occur together. The objective of this study is to use a wide range of CVD risk factors and outcomes to ...evaluate potential total and direct causal roles of alcohol and tobacco use on CVD risk factors and events.
Using large publicly available genome-wide association studies (GWASs) (results from more than 1.2 million combined study participants) of predominantly European ancestry, we conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to simultaneously assess the independent impact of alcohol consumption and smoking on a wide range of CVD risk factors and outcomes. Multiple sensitivity analyses, including complementary Mendelian randomization (MR) methods, and secondary alcohol consumption and smoking datasets were used. SVMR showed genetic predisposition for alcohol consumption to be associated with CVD risk factors, including high-density lipoprotein cholesterol (HDL-C) (beta 0.40, 95% confidence interval (CI), 0.04-0.47, P value = 1.72 × 10-28), triglycerides (TRG) (beta -0.23, 95% CI, -0.30, -0.15, P value = 4.69 × 10-10), automated systolic blood pressure (BP) measurement (beta 0.11, 95% CI, 0.03-0.18, P value = 4.72 × 10-3), and automated diastolic BP measurement (beta 0.09, 95% CI, 0.03-0.16, P value = 5.24 × 10-3). Conversely, genetically predicted smoking was associated with increased TRG (beta 0.097, 95% CI, 0.014-0.027, P value = 6.59 × 10-12). Alcohol consumption was also associated with increased myocardial infarction (MI) and coronary heart disease (CHD) risks (MI odds ratio (OR) = 1.24, 95% CI, 1.03-1.50, P value = 0.02; CHD OR = 1.21, 95% CI, 1.01-1.45, P value = 0.04); however, its impact was attenuated in MVMR adjusting for smoking. Conversely, alcohol maintained an association with coronary atherosclerosis (OR 1.02, 95% CI, 1.01-1.03, P value = 5.56 × 10-4). In comparison, after adjusting for alcohol consumption, smoking retained its association with several CVD outcomes including MI (OR = 1.84, 95% CI, 1.43, 2.37, P value = 2.0 × 10-6), CHD (OR = 1.64, 95% CI, 1.28-2.09, P value = 8.07 × 10-5), heart failure (HF) (OR = 1.61, 95% CI, 1.32-1.95, P value = 1.9 × 10-6), and large artery atherosclerosis (OR = 2.4, 95% CI, 1.41-4.07, P value = 0.003). Notably, using the FinnGen cohort data, we were able to replicate the association between smoking and several CVD outcomes including MI (OR = 1.77, 95% CI, 1.10-2.84, P value = 0.02), HF (OR = 1.67, 95% CI, 1.14-2.46, P value = 0.008), and peripheral artery disease (PAD) (OR = 2.35, 95% CI, 1.38-4.01, P value = 0.002). The main limitations of this study include possible bias from unmeasured confounders, inability of summary-level MR to investigate a potentially nonlinear relationship between alcohol consumption and CVD risk, and the generalizability of the UK Biobank (UKB) to other populations.
Evaluating the widest range of CVD risk factors and outcomes of any alcohol consumption or smoking MR study to date, we failed to find a cardioprotective impact of genetically predicted alcohol consumption on CVD outcomes. However, alcohol was associated with and increased HDL-C, decreased TRG, and increased BP, which may indicate pathways through impact CVD risk, warranting further study. We found smoking to be a risk factor for many CVDs even after adjusting for alcohol. While future studies incorporating alcohol consumption patterns are necessary, our data suggest causal inference between alcohol, smoking, and CVD risk, further supporting that lifestyle modifications might be able to reduce overall CVD risk.
Alcohol use disorder (AUD) is defined by several symptom criteria, which can be dissected further at the genetic level. Over the past several years, our understanding of the genetic factors ...influencing alcohol use and abuse has progressed tremendously; numerous loci have been implicated in different aspects of alcohol use. Previously known associations with alcohol-metabolizing enzymes (ADH1B, ALDH2) have been replicated definitively. In addition, novel associations with loci containing the genes KLB, GCKR, CRHR1, and CADM2 have been reported. Downstream analyses have leveraged these genetic findings to reveal important relationships between alcohol use behaviors and both physical and mental health. AUD and aspects of alcohol misuse have been shown to overlap strongly with psychiatric disorders, whereas aspects of alcohol consumption have shown stronger links to metabolism. These results demonstrate that the genetic architecture of alcohol consumption only partially overlaps with the genetics of clinically defined AUD. We discuss the limitations of using quantitative measures of alcohol use as proxy measures for AUD, and we outline how future studies will require careful phenotype harmonization to properly capture the genetic liability to AUD.
Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is ...not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.
Alcohol use disorders are common conditions that have enormous social and economic consequences. Genome-wide association analyses were performed to identify genetic variants associated with a proxy ...measure of alcohol consumption and alcohol misuse and to explore the shared genetic basis between these measures and other substance use, psychiatric, and behavioral traits.
This study used quantitative measures from the Alcohol Use Disorders Identification Test (AUDIT) from two population-based cohorts of European ancestry (UK Biobank N=121,604 and 23andMe N=20,328) and performed a genome-wide association study (GWAS) meta-analysis. Two additional GWAS analyses were performed, a GWAS for AUDIT scores on items 1-3, which focus on consumption (AUDIT-C), and for scores on items 4-10, which focus on the problematic consequences of drinking (AUDIT-P).
The GWAS meta-analysis of AUDIT total score identified 10 associated risk loci. Novel associations localized to genes including JCAD and SLC39A13; this study also replicated previously identified signals in the genes ADH1B, ADH1C, KLB, and GCKR. The dimensions of AUDIT showed positive genetic correlations with alcohol consumption (r
=0.76-0.92) and DSM-IV alcohol dependence (r
=0.33-0.63). AUDIT-P and AUDIT-C scores showed significantly different patterns of association across a number of traits, including psychiatric disorders. AUDIT-P score was significantly positively genetically correlated with schizophrenia (r
=0.22), major depressive disorder (r
=0.26), and attention deficit hyperactivity disorder (r
=0.23), whereas AUDIT-C score was significantly negatively genetically correlated with major depressive disorder (r
=-0.24) and ADHD (r
=-0.10). This study also used the AUDIT data in the UK Biobank to identify thresholds for dichotomizing AUDIT total score that optimize genetic correlations with DSM-IV alcohol dependence. Coding individuals with AUDIT total scores ≤4 as control subjects and those with scores ≥12 as case subjects produced a significant high genetic correlation with DSM-IV alcohol dependence (r
=0.82) while retaining most subjects.
AUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and alcohol use disorders.
'Epigenetic age acceleration' is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used ...measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC, TPMT) and immune system pathways (TRIM59, EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3, MANBA, TRIM46), with metabolic functions (UBE2D3, MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father's age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.
Neuroticism is a relatively stable personality trait characterized by negative emotionality (for example, worry and guilt)
; heritability estimated from twin studies ranges from 30 to 50%
, and ...SNP-based heritability ranges from 6 to 15%
. Increased neuroticism is associated with poorer mental and physical health
, translating to high economic burden
. Genome-wide association studies (GWAS) of neuroticism have identified up to 11 associated genetic loci
. Here we report 116 significant independent loci from a GWAS of neuroticism in 329,821 UK Biobank participants; 15 of these loci replicated at P < 0.00045 in an unrelated cohort (N = 122,867). Genetic signals were enriched in neuronal genesis and differentiation pathways, and substantial genetic correlations were found between neuroticism and depressive symptoms (r
= 0.82, standard error (s.e.) = 0.03), major depressive disorder (MDD; r
= 0.69, s.e. = 0.07) and subjective well-being (r
= -0.68, s.e. = 0.03) alongside other mental health traits. These discoveries significantly advance understanding of neuroticism and its association with MDD.
Observational studies suggest that lower educational attainment (EA) may be associated with risky alcohol use behaviors; however, these findings may be biased by confounding and reverse causality. We ...performed two-sample Mendelian randomization (MR) using summary statistics from recent genome-wide association studies (GWAS) with >780,000 participants to assess the causal effects of EA on alcohol use behaviors and alcohol dependence (AD). Fifty-three independent genome-wide significant SNPs previously associated with EA were tested for association with alcohol use behaviors. We show that while genetic instruments associated with increased EA are not associated with total amount of weekly drinks, they are associated with reduced frequency of binge drinking ≥6 drinks (ß
= -0.198, 95% CI, -0.297 to -0.099, P
= 9.14 × 10
), reduced total drinks consumed per drinking day (ß
= -0.207, 95% CI, -0.293 to -0.120, P
= 2.87 × 10
), as well as lower weekly distilled spirits intake (ß
= -0.148, 95% CI, -0.188 to -0.107, P
= 6.24 × 10
). Conversely, genetic instruments for increased EA were associated with increased alcohol intake frequency (ß
= 0.331, 95% CI, 0.267-0.396, P
= 4.62 × 10
), and increased weekly white wine (ß
= 0.199, 95% CI, 0.159-0.238, P
= 7.96 × 10
) and red wine intake (ß
= 0.204, 95% CI, 0.161-0.248, P
= 6.67 × 10
). Genetic instruments associated with increased EA reduced AD risk: an additional 3.61 years schooling reduced the risk by ~50% (OR
= 0.508, 95% CI, 0.315-0.819, P
= 5.52 × 10
). Consistency of results across complementary MR methods accommodating different assumptions about genetic pleiotropy strengthened causal inference. Our findings suggest EA may have important effects on alcohol consumption patterns and may provide potential mechanisms explaining reported associations between EA and adverse health outcomes.
Variation in DNA methylation (DNAm) is associated with lifestyle factors such as smoking and body mass index (BMI) but there has been little research exploring its ability to identify individuals ...with major depressive disorder (MDD). Using penalised regression on genome-wide CpG methylation, we tested whether DNAm risk scores (MRS), trained on 1223 MDD cases and 1824 controls, could discriminate between cases (n = 363) and controls (n = 1417) in an independent sample, comparing their predictive accuracy to polygenic risk scores (PRS). The MRS explained 1.75% of the variance in MDD (β = 0.338, p = 1.17 × 10
) and remained associated after adjustment for lifestyle factors (β = 0.219, p = 0.001, R
= 0.68%). When modelled alongside PRS (β = 0.384, p = 4.69 × 10
) the MRS remained associated with MDD (β = 0.327, p = 5.66 × 10
). The MRS was also associated with incident cases of MDD who were well at recruitment but went on to develop MDD at a later assessment (β = 0.193, p = 0.016, R
= 0.52%). Heritability analyses found additive genetic effects explained 22% of variance in the MRS, with a further 19% explained by pedigree-associated genetic effects and 16% by the shared couple environment. Smoking status was also strongly associated with MRS (β = 0.440, p ≤ 2 × 10
). After removing smokers from the training set, the MRS strongly associated with BMI (β = 0.053, p = 0.021). We tested the association of MRS with 61 behavioural phenotypes and found that whilst PRS were associated with psychosocial and mental health phenotypes, MRS were more strongly associated with lifestyle and sociodemographic factors. DNAm-based risk scores of MDD significantly discriminated MDD cases from controls in an independent dataset and may represent an archive of exposures to lifestyle factors that are relevant to the prediction of MDD.
Phytophthora ramorum is an invasive pathogen responsible for extensive mortality in larches in the United Kingdom. There is great interest from the forestry industry in the possibility of selection ...for resistance to P. ramorum in Japanese larch in order to retain it as a commercially viable species. This study is the first to investigate variation in resistance to P. ramorum among planted populations of Japanese larch in the UK. Our study uses inoculation of excised material from putatively resistant survivor trees and known susceptible trees. We found variation in susceptibility to P. ramorum within Japanese larch stands planted in the Galloway forest of Scotland with some trees showing significantly shorter lesion development than others, from a mean lesion length of 34.7 mm in the least susceptible clone to 135 mm in the most susceptible. Although clones from the putatively resistant and known susceptible groups were not significantly different (p = .055), we propose that survivor trees include a higher proportion of resistant or low susceptibility trees and would be a useful starting point for further work investigating natural resistance in larch.
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