Quantifying the Relative Importance of Genetics and Environment on the Comorbidity between Mental- and Cardiometabolic Disorders: A Comprehensive Analysis of National Register Data from 17 million Scandinavians.

Mental disorders (MDs) are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders (CMDs). Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records and complete genealogies of Denmark and Sweden (n=17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six MDs and 14 CMDs. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with CMDs, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with CMDs was mainly or fully driven by environmental factors. These findings provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders.

Contributions of Polygenic Risk and Disease Status to Gray Matter Abnormalities in Major Depression.

BACKGROUND: Gray matter (GM) abnormalities in depression are potentially attributable to some combination of trait, state, and illness history factors. Here, we sought to determine the contributions of polygenic risk for depression, depressive disease status, and the interaction of these factors to these GM abnormalities. METHODS: We conducted a cross-sectional comparison using a 2 × 3 factorial design examining effects of polygenic risk for depression (lower vs. upper quartile) and depression status (never depressed, currently depressed, or remitted depression) on regional GM concentration and GM volume. Participants were a subset of magnetic resonance imaging-scanned UK Biobank participants comprising 2682 people (876 men, 1806 women) algorithmically matched on 16 potential confounders. RESULTS: In women but not men, we observed that elevated polygenic risk for depression was associated with reduced cerebellar GM volume. This deficit occurred in salience and dorsal attention network regions of the cerebellum and was associated with poorer performance on tests of attention and executive function but not fluid intelligence. Moreover, in women with current depression compared to both women with remitted depression and women who never had depression, we observed GM reductions in ventral and medial prefrontal, insular, and medial temporal regions. These state-related abnormalities remained when accounting for antidepressant medication status. CONCLUSIONS: Neuroanatomical deficits attributed broadly to major depression are more likely due to an aggregation of independent factors. Polygenic risk for depression accounted for cerebellar structural abnormalities that themselves accounted for cognitive deficits observed in this disorder. Medial and ventral prefrontal, insular, and temporal cortex deficits constituted a much larger proportion of the aggregate deficit and were attributable to the depressed state.

Influence of vowels on note pitching in a cappella vocal quartet performance.

This paper notes that accurate tuning in a cappella (unaccompanied) choral music is a two-step process requiring (1) making pitch shifts on individual notes to sing intervals in just intonation thereby providing beat-free tuning for the consonant musical intervals that underpin the underlying harmony and (2) tuning different vowels to account for any additional pitch changes that are made in the context of the intrinsic pitch relating to the specific vowel being produced. This paper explores the second of these in the context of a part-by-part vowel variation during a sustained chord sung by the other three parts by a quartet of professional singers. OBJECTIVE: This study aimed to investigate the relationship between the fundamental frequencies employed when singing different vowels on the same pitch for each member in turn of a professional soprano, alto, tenor, bass (SATB) a cappella vocal quartet in terms of the measured fundamental frequency during the production of a set of individual vowels within a four-part carrier phrase. STUDY DESIGN: This is an experimental singing production study on the tuning of vowels in the context of a cappella quartet singing. To facilitate this, one singer at a time in a professional a cappella vocal quartet changed the vowel they are singing on a single note concurrent with a consonant a cappella triad being sustained by the other three singers singing a fixed vowel. METHODS/DESIGN: The first few bars of the a cappella anthem "If ye love me" by Thomas Tallis provided a carrier phrase that ended with a held chord on the chord on the word "me" by three singers against which the remaining singer produced a set of different vowels on their note of the chord. This is carried out for each of the four singers. The hypothesis being investigated is to remain accurately in-tune; fundamental frequency should be varied depending on the vowel being sung. Fundamental frequencies were measured using electrolaryngographs to ensure that there was no acoustic interference that could affect the accuracy of the fundamental frequency measurements if they were obtained from the audio output. RESULTS: The results provide clear evidence of changes being made to the fundamental frequencies of different vowels in an a cappella quartet context, and these changes confirm variations found elsewhere relating to the perceived pitches of different vowels. CONCLUSIONS: Measurable and consistent fundamental frequency variations occur when one part tunes different vowels against a reference chord sung by the other three singers in a choral quartet context on a fixed vowel. This has a direct consequence for tuning in a cappella choral music. The importance of carefully tuning individual notes for different vowels in a cappella choral singing requires focused listening to the pitches of the sounds being produced by the other singers in the choir. Usually, all parts are singing common vowels where it is important that the vowels are matched by being carefully blended together and tuning is aimed at being beat-free in just intonation. When compositions require parts to sing different vowels, both intrinsic (production related) and auditory (hearing related) pitch variations become relevant and challenge beat-free tuning.

A sex-specific genome-wide association study of depression phenotypes in UK Biobank.

There are marked sex differences in the prevalence, phenotypic presentation and treatment response for major depression. While genome-wide association studies (GWAS) adjust for sex differences, to date, no studies seek to identify sex-specific markers and pathways. In this study, we performed a sex-stratified genome-wide association analysis for broad depression with the UK Biobank total participants (N = 274,141), including only non-related participants, as well as with males (N = 127,867) and females (N = 146,274) separately. Bioinformatics analyses were performed to characterize common and sex-specific markers and associated processes/pathways. We identified 11 loci passing genome-level significance (P < 5 × 10-8) in females and one in males. In both males and females, genetic correlations were significant between the broad depression GWA and other psychopathologies; however, correlations with educational attainment and metabolic features including body fat, waist circumference, waist-to-hip ratio and triglycerides were significant only in females. Gene-based analysis showed 147 genes significantly associated with broad depression in the total sample, 64 in the females and 53 in the males. Gene-based analysis revealed "Regulation of Gene Expression" as a common biological process, but suggested sex-specific molecular mechanisms. Finally, sex-specific polygenic risk scores (PRSs) for broad depression outperformed total and the opposite sex PRSs in the prediction of broad major depressive disorder. These findings provide evidence for sex-dependent genetic pathways for clinical depression as well as for health conditions comorbid with depression.

Common and rare variant associations with latent traits underlying depression, bipolar disorder, and schizophrenia.

Genetic studies in psychiatry have primarily focused on the effects of common genetic variants, but few have investigated the role of rare genetic variants, particularly for major depression. In order to explore the role of rare variants in the gap between estimates of single nucleotide polymorphism (SNP) heritability and twin study heritability, we examined the contribution of common and rare genetic variants to latent traits underlying psychiatric disorders using high-quality imputed genotype data from the UK Biobank. Using a pre-registered analysis, we used items from the UK Biobank Mental Health Questionnaire relevant to three psychiatric disorders: major depression (N = 134,463), bipolar disorder (N = 117,376) and schizophrenia (N = 130,013) and identified a general hierarchical factor for each that described participants' responses. We calculated participants' scores on these latent traits and conducted single-variant genetic association testing (MAF > 0.05%), gene-based burden testing and pathway association testing associations with these latent traits. We tested for enrichment of rare variants (MAF 0.05-1%) in genes that had been previously identified by common variant genome-wide association studies, and genes previously associated with Mendelian disorders having relevant symptoms. We found moderate genetic correlations between the latent traits in our study and case-control phenotypes in previous genome-wide association studies, and identified one common genetic variant (rs72657988, minor allele frequency = 8.23%, p = 1.01 × 10-9) associated with the general factor of schizophrenia, but no other single variants, genes or pathways passed significance thresholds in this analysis, and we did not find enrichment in previously identified genes.

An Investigation in the Measurable Differences between Pitch Perception in the Voice and Pitch Perception of External Sound Sources.

OBJECTIVES: Pitch perception is an important part of accurate singing. Therefore, accurate singing requires the ability to accurately assess the pitch in one's own voice.There are two objectives of this study the first was to investigate whether there is a measurable difference in perceived pitch in one's voice to the pitch one perceives from an external sound source. The second, to measure the effects of occlusion on pitch accuracy over a melodic phrase. STUDY DESIGN: We recruited 16 participants for this study. The study that was designed to investigate the perceptual difference was split into two parts. The first is a one-to-one pitch matching test where they would recreate a pitch with singing and matching external pitches. The second was singing the familiar song 'Happy Birthday' which was used to measure pitch accuracy over a melodic phrase and to measure the effects of occlusion on pitch accuracy while singing. METHODS: The one-to-one study involved singing back a series of 5 notes to a set vowel which were the same 5 notes used when matching them to a series of possible pitches on the button test. The melodic test was to sing 'Happy Birthday' 3 times, the first normally, the second wearing headphones to occlude the ear to reduce air conductive hearing and the third time with white noise to mask all hearing. RESULTS: The results showed a higher accuracy of pitch matching with external sounds over using their voice, and some form of occlusion (wearing headphones or headphones with white noise) showed the version with higher pitch accuracy. CONCLUSIONS: The results of this study showed that there was improved pitch accuracy when comparing two external sounds in pitch and when singing occlusion of some form improved pitch accuracy. This could suggest a difference when recreating pitch between the voice and matching external sound sources. Furthermore, with the improvements shown from occluding the ears, it could further suggest a difference in pitch perception abilities between the voice and external sound sources. This could have implications of improving pitch accuracy in a studio environment.

The Dynamic Effect of the Valleculae on Singing Voice - An Exploratory Study Using 3D Printed Vocal Tracts.

BACKGROUND AND OBJECTIVES: The valleculae can be seen as a pair of side branches of the human vocal tract like the piriform fossae. While the acoustic properties of the piriform fossae have been explored in detail, there is little evidence of full exploration of the acoustic properties of the valleculae. A recent investigation (Vampola, Horácek, & Svec, 2015), using a finite element model of a single vowel /a/, suggests that the valleculae created two antiresonances and two resonances in the high frequency region (above 4kHz) along with those produced by the piriform sinuses. In the current study, we investigate, in multiple vowels, the acoustic influences of the valleculae in singing voice, using 3-D printed vocal tracts. METHOD: MRI data were collected from an operatic tenor singing English vowels /a/, /u/, /i/. The images of each vowel were segmented and edited to create a pair of tracts, where one is the original and one had the valleculae digitally removed.The printed tracts were then placed atop a vocal tract organ loudspeaker, excited by white noise. Recordings were made with a microphone placed in front of the mouths of the tracts, to measure their frequency responses. RESULTS: Dimensional changes were observed in valleculae of different vowels, with the long-term average spectra of the recordings illustrating clear differences between the frequency responses of the va-nova (valleculae - no valleculae) pairs, which varies with vowels. CONCLUSION: The experiment demonstrates the dynamic1 nature of the shapes of the valleculae in the human vocal tract and its acoustic consequences. It provides evidence that the valleculae have similar acoustic properties to the piriform fossae but with larger variations, and in some cases can influence acoustically the frequency region below 4kHz. The results suggest that large volume valleculae have the potential to impede to some extent the acoustic effect of the singers formant cluster and small valleculae may do the reverse. Since the volume of the valleculae is observed to be largely dependent on tongue movement and also with changes to the uttered vowel, it can be assumed that the high frequency energy, including that within the singer's formant region, could be vowel dependent. Strategies to control valleculae volumes are likely to be highly relevant to voice pedagogy practice as well as singing performance.

Polygenic risk scores for schizophrenia and major depression are associated with socio-economic indicators of adversity in two British community samples.

Schizophrenia (SCZ) and major depressive disorder (MDD) are complex psychiatric disorders which contribute substantially to the global burden of disease. Both psychopathologies are heritable with some genetic overlap between them. Importantly, SCZ and MDD have also been found to be associated with environmental risk factors. However, rather than being independent of genetic influences, exposure to environmental risk factors may be under genetic control, known as gene-environment correlation (rGE). In this study we investigated rGE in relation to polygenic risk scores for SCZ and MDD in adults, derived from large genome-wide association studies, across two different British community samples: Understanding Society (USoc) and the National Child Development Study (NCDS). We tested whether established environmental risk factors for SCZ and/or MDD are correlated with polygenic scores in adults and whether these associations differ between the two disorders and cohorts. Findings partially overlapped between disorders and cohorts. In NCDS, we identified a significant correlation between the genetic risk for MDD and an indicator of low socio-economic status, but no significant findings emerged for SCZ. In USoc, we replicated associations between indicators of low socio-economic status and the genetic propensity for MDD. In addition, we identified associations between the genetic susceptibility for SCZ and being single or divorced. Results across both studies provide further evidence that the genetic risk for SCZ and MDD were associated with common environmental risk factors, specifically MDD's association with lower socio-economic status.

Local CpG density affects the trajectory and variance of age-associated DNA methylation changes.

BACKGROUND: DNA methylation is an epigenetic mark associated with the repression of gene promoters. Its pattern in the genome is disrupted with age and these changes can be used to statistically predict age with epigenetic clocks. Altered rates of aging inferred from these clocks are observed in human disease. However, the molecular mechanisms underpinning age-associated DNA methylation changes remain unknown. Local DNA sequence can program steady-state DNA methylation levels, but how it influences age-associated methylation changes is unknown. RESULTS: We analyze longitudinal human DNA methylation trajectories at 345,895 CpGs from 600 individuals aged between 67 and 80 to understand the factors responsible for age-associated epigenetic changes at individual CpGs. We show that changes in methylation with age occur at 182,760 loci largely independently of variation in cell type proportions. These changes are especially apparent at 8322 low CpG density loci. Using SNP data from the same individuals, we demonstrate that methylation trajectories are affected by local sequence polymorphisms at 1487 low CpG density loci. More generally, we find that low CpG density regions are particularly prone to change and do so variably between individuals in people aged over 65. This differs from the behavior of these regions in younger individuals where they predominantly lose methylation. CONCLUSIONS: Our results, which we reproduce in two independent groups of individuals, demonstrate that local DNA sequence influences age-associated DNA methylation changes in humans in vivo. We suggest that this occurs because interactions between CpGs reinforce maintenance of methylation patterns in CpG dense regions.

Gene-Environment Correlation over Time: A Longitudinal Analysis of Polygenic Risk Scores for Schizophrenia and Major Depression in Three British Cohorts Studies.

Research suggests that both genetic and environmental risk factors are involved in the aetiology of schizophrenia (SCZ) and major depressive disorder (MDD). Importantly, environmental and genetic risk factors are often related as evidenced in gene-environment correlation (rGE), which describes the observation that genetic and environmental factors are associated with each other. It is understood that rGE gets stronger over time as individuals select their environments more actively based on their genetic propensities. However, little is known whether rGEs remain stable over time or change across different development periods. Using data from three British longitudinal cohorts, we investigated whether rGE patterns of polygenic risk scores (PRS) for SCZ and MDD changed over time across childhood and adulthood, as well as across both from birth to age 55 and whether results differed between SCZ and MDD. Overall, the majority of rGEs remained stable across the investigated development periods. Furthermore, the few detected rGE changes which did differ between SCZ and MDD, could not be explained by the confounding of clinical cases and are therefore likely the result of actual changes in environmental and cultural risk factors with genetic susceptibility to SCZ and MDD likely playing a less significant role.

Developmental History of the Vocal Tract Organ.

OBJECTIVES: The Vocal Tract Organ has had a number of iterations resulting from advances in available technology as well as requirements of perceptual experiments and performance paradigms. The objective of this paper is to relate the development history of the Vocal Tract Organ from the original vision to what it is today as a modern version of the Vox Humana pipe organ stop for application in voice production and perception research. STUDY DESIGN: Descriptive METHODS/DESIGN: The latest Vocal Tract Organ is a polyphonic eight-channel eight-stop one manual Vocal Tract Organ that enables tab stop selected three-D printed vocal tracts to be used to create sound. This version includes eight stops (four for female vowel oral tracts and four for male vowel oral tracts). The stops are implemented using conventionally engraved pipe organ stop tabs labeled "Vox Humana Female" or "Vox Humana Male" followed by the three-D printed vowel: "EE", "AH", "ER" or "UU." This is described alongside the development stages from which it emerged and covers all previous versions of the Vocal Tract Organ. At the heart of the latest instrument is a Bela BeagleBone Black with a Bela cape audio expander board which incorporates eight 16-bit audio outputs at 44.1 kHz sampling rate (earlier versions based on the Arduino Mega board were limited to 8-bit audio at an audio sampling rate of 16.384 kHz which limited the overall output spectrum). The latest Vocal Tract Organ is programmed using the audio graphical programming language Pure Data which is directly compatible with the Bela system. The Pure Data patch creates eight larynx outputs at the pitches set by the keys depressed on the keyboard and these are routed to Vocal Tract Organ loudspeakers with three-D printed vocal tracts attached. RESULTS: The Bela system has enabled real-time synthesis of eight-note polyphonic sounds to eight separate three-D printed vocal tracts, each being selectable via an organ tab stop switch. The instrument has been cased in a purpose-designed and built prototype laser-cut enclosure that incorporates the eight tab stops, a MIDI keyboard input, a pipe organ style swell (volume) pedal connection, four stereo (eight channels) audio amplifiers and terminal connections for the eight loudspeakers. CONCLUSIONS: The Vocal Tract Organ functions as a musical instrument for performance and as an instrument for vowel and pitch perception research. Implementing it with the Bela family of processors allows for low audio latency of 1 ms and rapid prototyping due to being able to program directly with the high-level graphical audio programming language, Pure data (Pd).

Polygenic scores for schizophrenia and major depression are associated with psychosocial risk factors in children: evidence of gene-environment correlation.

BACKGROUND: Whilst genetic and environmental risk factors for schizophrenia (SCZ) and major depressive disorder (MDD) have been established, it is unclear whether exposure to environmental risk factors is genetically confounded by passive, evocative or active gene-environment correlation (rGE). STUDY OBJECTIVE: This study aims to investigate: (a) whether the genetic risk for SCZ/MDD in children is correlated with established environmental and psychosocial risk factors in two British community samples, the 1958 National Child Development Study (NCDS) and the Millennium Cohort Study (MCS), (b) whether these associations vary between both psychopathologies, and (c) whether findings differ across the two cohorts which were born 42 years apart. METHODS: Polygenic risk scores (PRS) from existing large genome-wide associations studies (GWAS) were applied to test the correlation between the child genetic risk for SCZ/MDD and known environmental risk factors. In addition, parental and child genetic data from MCS were used to distinguish between passive and evocative rGE. RESULTS: The child polygenic risk for SCZ and MDD was correlated with single parenthood in MCS. Moreover, the lack of father's involvement in child care was associated with the genetic risk for SCZ in NCDS. However, we also found associations between several indicators of low socioeconomic status and heightened genetic risk for MDD in children in both cohorts. Further, the genetic risk for MDD was associated with parental lack of interest in the child's education in NCDS as well as more maternal smoking and less maternal alcohol consumption during childhood in MCS. According to sensitivity analyses in MCS (controlling for parental genotype), more than half of our significant correlations reflected passive rGE. CONCLUSIONS: Findings suggest that several established environmental and psychosocial risk factors for SCZ and MDD are at least partially associated with children's genetic risk for these psychiatric disorders.

Clarifying the causes of consistent and inconsistent findings in genetics.

As research in genetics has advanced, some findings have been unexpected or shown to be inconsistent between studies or datasets. The reasons these inconsistencies arise are complex. Results from genetic studies can be affected by various factors including statistical power, linkage disequilibrium, quality control, confounding and selection bias, as well as real differences from interactions and effect modifiers, which may be informative about the mechanisms of traits and disease. Statistical artefacts can manifest as differences between results but they can also conceal underlying differences, which implies that their critical examination is important for understanding the underpinnings of traits. In this review, we examine these factors and outline how they can be identified and conceptualised with structural causal models. We explain the consequences they have on genetic estimates, such as genetic associations, polygenic scores, family- and genome-wide heritability, and describe methods to address them to aid in the estimation of true effects of genetic variation. Clarifying these factors can help researchers anticipate when results are likely to diverge and aid researchers' understanding of causal relationships between genes and complex traits.

Complex trait methylation scores in the prediction of major depressive disorder.

BACKGROUND: DNA methylation (DNAm) is associated with time-varying environmental factors that contribute to major depressive disorder (MDD) risk. We sought to test whether DNAm signatures of lifestyle and biochemical factors were associated with MDD to reveal dynamic biomarkers of MDD risk that may be amenable to lifestyle interventions. METHODS: Here, we calculated methylation scores (MS) at multiple p-value thresholds for lifestyle (BMI, smoking, alcohol consumption, and educational attainment) and biochemical (high-density lipoprotein (HDL) and total cholesterol) factors in Generation Scotland (GS) (N=9,502) and in a replication cohort (ALSPACadults, N=565), using CpG sites reported in previous well-powered methylome-wide association studies. We also compared their predictive accuracy for MDD to a MDD MS in an independent GS sub-sample (N=4,432). FINDINGS: Each trait MS was significantly associated with its corresponding phenotype in GS (ßrange=0.089-1.457) and in ALSPAC (ßrange=0.078-2.533). Each MS was also significantly associated with MDD before and after adjustment for its corresponding phenotype in GS (ßrange=0.053-0.145). After accounting for relevant lifestyle factors, MS for educational attainment (ß=0.094) and alcohol consumption (MSp-value<0.01-0.5; ßrange=-0.069-0.083) remained significantly associated with MDD in GS. Smoking (AUC=0.569) and educational attainment (AUC=0.585) MSs could discriminate MDD from controls better than the MDD MS (AUC=0.553) in the independent GS sub-sample. Analyses implicating MDD did not replicate across ALSPAC, although the direction of effect was consistent for all traits when adjusting for the MS corresponding phenotypes. INTERPRETATION: We showed that lifestyle and biochemical MS were associated with MDD before and after adjustment for their corresponding phenotypes (pnominal<0.05), but not when smoking, alcohol consumption, and BMI were also included as covariates. MDD results did not replicate in the smaller, female-only independent ALSPAC cohort (NALSPAC=565; NGS=9,502), potentially due to demographic differences or low statistical power, but effect sizes were consistent with the direction reported in GS. DNAm scores for modifiable MDD risk factors may contribute to disease vulnerability and, in some cases, explain additional variance to their observed phenotypes. FUNDING: Wellcome Trust.

Exploring polygenic-environment and residual-environment interactions for depressive symptoms within the UK Biobank.

Substantial advances have been made in identifying genetic contributions to depression, but little is known about how the effect of genes can be modulated by the environment, creating a gene-environment interaction. Using multivariate reaction norm models (MRNMs) within the UK Biobank (N = 61294-91644), we investigate whether the polygenic and residual variance components of depressive symptoms are modulated by 17 a priori selected covariate traits-12 environmental variables and 5 biomarkers. MRNMs, a mixed-effects modelling approach, provide unbiased polygenic-covariate interaction estimates for a quantitative trait by controlling for outcome-covariate correlations and residual-covariate interactions. A continuous depressive symptom variable was the outcome in 17 MRNMs-one for each covariate trait. Each MRNM had a fixed-effects model (fixed effects included the covariate trait, demographic variables, and principal components) and a random effects model (where polygenic-covariate and residual-covariate interactions are modelled). Of the 17 selected covariates, 11 significantly modulate deviations in depressive symptoms through the modelled interactions, but no single interaction explains a large proportion of phenotypic variation. Results are dominated by residual-covariate interactions, suggesting that covariate traits (including neuroticism, childhood trauma, and BMI) typically interact with unmodelled variables, rather than a genome-wide polygenic component, to influence depressive symptoms. Only average sleep duration has a polygenic-covariate interaction explaining a demonstrably nonzero proportion of the variability in depressive symptoms. This effect is small, accounting for only 1.22% (95% confidence interval: [0.54, 1.89]) of variation. The presence of an interaction highlights a specific focus for intervention, but the negative results here indicate a limited contribution from polygenic-environment interactions.

Effects of depression on employment and social outcomes: a Mendelian randomisation study.

BACKGROUND: Depression is associated with socioeconomic disadvantage. However, whether and how depression exerts a causal effect on employment remains unclear. We used Mendelian randomisation (MR) to investigate whether depression affects employment and related outcomes in the UK Biobank dataset. METHODS: We selected 227 242 working-age participants (40-64 in men, 40-59 years for women) of white British ethnicity/ancestry with suitable genetic data in the UK Biobank study. We used 30 independent genetic variants associated with depression as instruments. We conducted observational and two-sample MR analyses. Outcomes were employment status (employed vs not, and employed vs sickness/disability, unemployment, retirement or caring for home/family); weekly hours worked (among employed); Townsend Deprivation Index; highest educational attainment; and household income. RESULTS: People who had experienced depression had higher odds of non-employment, sickness/disability, unemployment, caring for home/family and early retirement. Depression was associated with reduced weekly hours worked, lower household income and lower educational attainment, and increased deprivation. MR analyses suggested depression liability caused increased non-employment (OR 1.16, 95% CI 1.06 to 1.26) and sickness/disability (OR 1.56, 95% CI 1.34 to 1.82), but was not causal for caring for home/family, early retirement or unemployment. There was little evidence from MR that depression affected weekly hours worked, educational attainment, household income or deprivation. CONCLUSIONS: Depression liability appears to cause increased non-employment, particularly by increasing disability. There was little evidence of depression affecting early retirement, hours worked or household income, but power was low. Effective treatment of depression might have important economic benefits to individuals and society.

Using major depression polygenic risk scores to explore the depressive symptom continuum.

BACKGROUND: Major depression (MD) is often characterised as a categorical disorder; however, observational studies comparing sub-threshold and clinical depression suggest MD is continuous. Many of these studies do not explore the full continuum and are yet to consider genetics as a risk factor. This study sought to understand if polygenic risk for MD could provide insight into the continuous nature of depression. METHODS: Factor analysis on symptom-level data from the UK Biobank (N = 148 957) was used to derive continuous depression phenotypes which were tested for association with polygenic risk scores (PRS) for a categorical definition of MD (N = 119 692). RESULTS: Confirmatory factor analysis showed a five-factor hierarchical model, incorporating 15 of the original 18 items taken from the PHQ-9, GAD-7 and subjective well-being questionnaires, produced good fit to the observed covariance matrix (CFI = 0.992, TLI = 0.99, RMSEA = 0.038, SRMR = 0.031). MD PRS associated with each factor score (standardised ß range: 0.057-0.064) and the association remained when the sample was stratified into case- and control-only subsets. The case-only subset had an increased association compared to controls for all factors, shown via a significant interaction between lifetime MD diagnosis and MD PRS (p value range: 2.23 × 10-3-3.94 × 10-7). CONCLUSIONS: An association between MD PRS and a continuous phenotype of depressive symptoms in case- and control-only subsets provides support against a purely categorical phenotype; indicating further insights into MD can be obtained when this within-group variation is considered. The stronger association within cases suggests this variation may be of particular importance.

Methylome-wide association study of early life stressors and adult mental health.

The environment and events that we are exposed to in utero, during birth and in early childhood influence our future physical and mental health. The underlying mechanisms that lead to these outcomes are unclear, but long-term changes in epigenetic marks, such as DNA methylation, could act as a mediating factor or biomarker. DNA methylation data were assayed at 713 522 CpG sites from 9537 participants of the Generation Scotland: Scottish Family Health Study, a family-based cohort with extensive genetic, medical, family history and lifestyle information. Methylome-wide association studies of eight early life environment phenotypes and two adult mental health phenotypes (major depressive disorder and brief resilience scale) were conducted using DNA methylation data collected from adult whole blood samples. Two genes involved with different developmental pathways (PRICKLE2, Prickle Planar Cell Polarity Protein 2 and ABI1, Abl-Interactor-1) were annotated to CpG sites associated with preterm birth (P < 1.27 × 10-9). A further two genes important to the development of sensory pathways (SOBP, Sine Oculis Binding Protein Homolog and RPGRIP1, Retinitis Pigmentosa GTPase Regulator Interacting Protein) were annotated to sites associated with low birth weight (P < 4.35 × 10-8). The examination of methylation profile scores and genes and gene-sets annotated from associated CpGs sites found no evidence of overlap between the early life environment and mental health conditions. Birth date was associated with a significant difference in estimated lymphocyte and neutrophil counts. Previous studies have shown that early life environments influence the risk of developing mental health disorders later in life; however, this study found no evidence that this is mediated by stable changes to the methylome detectable in peripheral blood.

Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system.

Antidepressants are an effective treatment for major depressive disorder (MDD), although individual response is unpredictable and highly variable. Whilst the mode of action of antidepressants is incompletely understood, many medications are associated with changes in DNA methylation in genes that are plausibly linked to their mechanisms. Studies of DNA methylation may therefore reveal the biological processes underpinning the efficacy and side effects of antidepressants. We performed a methylome-wide association study (MWAS) of self-reported antidepressant use accounting for lifestyle factors and MDD in Generation Scotland (GS:SFHS, N = 6428, EPIC array) and the Netherlands Twin Register (NTR, N = 2449, 450 K array) and ran a meta-analysis of antidepressant use across these two cohorts. We found ten CpG sites significantly associated with self-reported antidepressant use in GS:SFHS, with the top CpG located within a gene previously associated with mental health disorders, ATP6V1B2 (ß = -0.055, pcorrected = 0.005). Other top loci were annotated to genes including CASP10, TMBIM1, MAPKAPK3, and HEBP2, which have previously been implicated in the innate immune response. Next, using penalised regression, we trained a methylation-based score of self-reported antidepressant use in a subset of 3799 GS:SFHS individuals that predicted antidepressant use in a second subset of GS:SFHS (N = 3360, ß = 0.377, p = 3.12 × 10-11, R2 = 2.12%). In an MWAS analysis of prescribed selective serotonin reuptake inhibitors, we showed convergent findings with those based on self-report. In NTR, we did not find any CpGs significantly associated with antidepressant use. The meta-analysis identified the two CpGs of the ten above that were common to the two arrays used as being significantly associated with antidepressant use, although the effect was in the opposite direction for one of them. Antidepressants were associated with epigenetic alterations in loci previously associated with mental health disorders and the innate immune system. These changes predicted self-reported antidepressant use in a subset of GS:SFHS and identified processes that may be relevant to our mechanistic understanding of clinically relevant antidepressant drug actions and side effects.

Epigenome-wide association study of alcohol consumption in N = 8161 individuals and relevance to alcohol use disorder pathophysiology: identification of the cystine/glutamate transporter SLC7A11 as a top target.

Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongly associated with alterations in DNA methylation. Identification of alcohol-associated methylomic variation might provide novel insights into pathophysiology and novel treatment targets for AUD. Here we performed the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N = 8161) and cross-validated findings in AUD populations with relevant endophenotypes, as well as alcohol-related animal models. Results showed 2504 CpGs significantly associated with alcohol consumption (Bonferroni p value < 6.8 × 10-8) with the five leading probes located in SLC7A11 (p = 7.75 × 10-108), JDP2 (p = 1.44 × 10-56), GAS5 (p = 2.71 × 10-47), TRA2B (p = 3.54 × 10-42), and SLC43A1 (p = 1.18 × 10-40). Genes annotated to associated CpG sites are implicated in liver and brain function, the cellular response to alcohol and alcohol-associated diseases, including hypertension and Alzheimer's disease. Two-sample Mendelian randomization confirmed the causal relationship of consumption on AUD risk (inverse variance weighted (IVW) p = 5.37 × 10-09). A methylation-based predictor of alcohol consumption was able to discriminate AUD cases in two independent cohorts (p = 6.32 × 10-38 and p = 5.41 × 10-14). The top EWAS probe cg06690548, located in the cystine/glutamate transporter SLC7A11, was replicated in an independent cohort of AUD and control participants (N = 615) and showed strong hypomethylation in AUD (p < 10-17). Decreased CpG methylation at this probe was consistently associated with clinical measures including increased heavy drinking days (p < 10-4), increased liver function enzymes (GGT (p = 1.03 × 10-21), ALT (p = 1.29 × 10-6), and AST (p = 1.97 × 10-8)) in individuals with AUD. Postmortem brain analyses documented increased SLC7A11 expression in the frontal cortex of individuals with AUD and animal models showed marked increased expression in liver, suggesting a mechanism by which alcohol leads to hypomethylation-induced overexpression of SLC7A11. Taken together, our EWAS discovery sample and subsequent validation of the top probe in AUD suggest a strong role of abnormal glutamate signaling mediated by methylomic variation in SLC7A11. Our data are intriguing given the prominent role of glutamate signaling in brain and liver and might provide an important target for therapeutic intervention.