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Antidepressant medications are frequently used as the first line of treatment for depression. However, their effectiveness is highly variable and influenced by genetic factors. Recently, pharmacogenetic studies, including candidate-gene, genome-wide association studies or polygenic risk scores, have attempted to uncover the genetic architecture of antidepressant response. Genetic variants in at least 27 genes are linked to antidepressant treatment response in both coding and non-coding genomic regions, but evidence is largely inconclusive due to the high polygenicity of the trait and limited cohort sizes in published studies. Future studies should increase the number and diversity of participants to yield sufficient statistical power to characterize the genetic underpinnings and biological mechanisms of treatment response, improve results generalizability and reduce racial health-related inequities.

Parkinson’s disease (PD) is a late-onset and genetically complex neurodegenerative disorder. Here we sought to identify genes and molecular pathways underlying the associations between PD and the volume of ten brain structures measured through magnetic resonance imaging (MRI) scans. We leveraged genome-wide genetic data from several cohorts, including the International Parkinson’s Disease Genomics Consortium (IPDG), the UK Biobank, the Adolescent Brain Cognitive Development (ABCD) study, the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), the Enhancing Neuroimaging Genetics through Meta-Analyses (ENIGMA), and 23andMe. We observed significant positive genetic correlations between PD and intracranial and subcortical brain volumes. Genome-wide association studies (GWAS) - pairwise analyses identified 210 genomic segments with shared aetiology between PD and at least one of these brain structures. Pathway enrichment results highlight potential links with chronic inflammation, the hypothalamic-pituitary-adrenal pathway, mitophagy, disrupted vesicle-trafficking, calcium-dependent, and autophagic pathways. Investigations for putative causal genetic effects suggest that a larger putamen volume could influence PD risk, independently of the potential causal genetic effects of intracranial volume (ICV) on PD. Our findings suggest that genetic variants influencing larger intracranial and subcortical brain volumes, possibly during earlier stages of life, influence the risk of developing PD later in life.

Stroke is the second leading cause of death and the third leading cause of long-term disability in the world. This study aimed to explore the novel putative causal genetic relationship of stroke with hundreds of complex traits by leveraging genetic data. We used genome-wide association studies (GWAS) data and the latent causal variable method to identify potential causal relationships between stroke and 1,504 complex traits of the UK biobank. We found that 262 traits were genetically correlated with stroke risk at a false discovery rate (FDR 0.60; FDR < 0.05). Our results showed that some conditions, including atrial fibrillation, pulmonary embolism, blood clots in the lung, platelet crit, self-reported deep venous thrombosis, weight gain after depression, and the use of some medications such as insulin, pioglitazone, and gliclazide were inferred to increase stroke risk. On the other hand, greater levels of testosterone, apolipoprotein A, SHBG, and HDL cholesterol decrease the risk of stroke. Also, our results suggest that genetic susceptibility to stroke raises the risk of neck and chest pain and loose teeth. Finally, our findings suggest that cardiac vascular disease, blood clot in lung, deep venous thrombosis, and certain anti-diabetic medications could have a causal role in increasing the risk of stroke, which could be used as novel testable hypotheses for future epidemiological studies.

Luminous infrared starbursts in the early Universe are thought to be the progenitors of massive quiescent galaxies identified at redshifts 2- 4. Using the Mid-IRfrared Instrument (MIRI) on board the James Webb Space Telescope (JWST), we present mid-infrared sub-arcsec imaging and spectroscopy of such a starburst: the slightly lensed hyper-luminous infrared system SPT0311-58 at z = 6.9. The MIRI IMager (MIRIM) and Medium Resolution Spectrometer (MRS) observations target the stellar (rest-frame 1.26 μm emission) structure and ionised (Paα and Hα) medium on kpc scales in the system. The MIRI observations are compared with existing ALMA far-infrared continuum and [C II]158μm imaging at a similar angular resolution. Even though the ALMA observations imply very high star formation rates (SFRs) in the eastern (E) and western (W) galaxies of the system, the Hα line is, strikingly, not detected in our MRS observations. This fact, together with the detection of the ionised gas phase in Paα, implies very high internal nebular extinction with lower limits (AV) of 4.2 (E) and 3.9 mag (W) as well as even larger values (5.6 (E) and 10.0 (W)) by spectral energy distribution (SED) fitting analysis. The extinction-corrected Paα lower limits of the SFRs are 383 and 230 M⊙ yr-1 for the E and W galaxies, respectively. This represents 50% of the SFRs derived from the [C II]158 μm line and infrared light for the E galaxy and as low as 6% for the W galaxy. The MIRIM observations reveal a clumpy stellar structure, with each clump having 3- 5× 109 M⊙ mass in stars, leading to a total stellar mass of 2.0 and 1.5× 1010 M⊙ for the E and W galaxies, respectively. The specific star formation (sSFR) in the stellar clumps ranges from 25 to 59 Gyr-1, assuming a star formation with a 50- 100 Myr constant rate. This sSFR is three to ten times larger than the values measured in galaxies of similar stellar mass at redshifts 6- 8. Thus, SPT0311-58 clearly stands out as a starburst system when compared with typical massive star-forming galaxies at similar high redshifts. The overall gas mass fraction is Mgas/M∗ ∼ 3, similar to that of z ∼ 4.5- 6 star-forming galaxies, suggesting a flattening of the gas mass fraction in massive starbursts up to redshift 7. The kinematics of the ionised gas in the E galaxy agrees with the known [C II] gas kinematics, indicating a physical association between the ionised gas and the cold ionised or neutral gas clumps. The situation in the W galaxy is more complex, as it appears to be a velocity offset by about +700 km s-1 in the Paα relative to the [C II] emitting gas. The nature of this offset and its reality are not fully established and require further investigation. The observed properties of SPT0311-58, such as the clumpy distribution at sub(kpc) scales and the very high average extinction, are similar to those observed in low- and intermediate-z luminous (E galaxy) and ultra-luminous (W galaxy) infrared galaxies, even though SPT0311-58 is observed only ∼800 Myr after the Big Bang. Such massive, heavily obscured clumpy starburst systems as SPT0311-58 likely represent the early phases in the formation of a massive high-redshift bulge, spheroids and/or luminous quasars. This study demonstrates that MIRI and JWST are, for the first time, able to explore the rest-frame near-infrared stellar and ionised gas structure of these galaxies, even during the Epoch of Reionization., Astronomy & Astrophysics, 671, ISSN:0004-6361, ISSN:1432-0746

Study ObjectivesDespite its association with severe health conditions, the etiology of sleep apnea (SA) remains understudied. This study sought to identify genetic variants robustly associated with SA risk.MethodsWe performed a genome-wide association study (GWAS) meta-analysis of SA across five cohorts (NTotal = 523 366), followed by a multi-trait analysis of GWAS (multi-trait analysis of genome-wide association summary statistics [MTAG]) to boost power, leveraging the high genetic correlation between SA and snoring. We then adjusted our results for the genetic effects of body mass index (BMI) using multi-trait-based conditional and joint analysis (mtCOJO) and sought replication of lead hits in a large cohort of participants from 23andMe, Inc (NTotal = 1 477 352; Ncases = 175 522). We also explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method.ResultsOur SA meta-analysis identified five independent variants with evidence of association beyond genome-wide significance. After adjustment for BMI, only one genome-wide significant variant was identified. MTAG analyses uncovered 49 significant independent loci associated with SA risk. Twenty-nine variants were replicated in the 23andMe GWAS adjusting for BMI. We observed genetic correlations with several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-associated conditions.ConclusionOur study uncovered multiple genetic loci associated with SA risk, thus increasing our understanding of the etiology of this condition and its relationship with other complex traits.

Attention Deficit-Hyperactivity Disorder (ADHD) is a complex psychiatric and neurodevelopmental disorder that develops during childhood and spans into adulthood. ADHD’s aetiology is complex, and evidence about its cause and risk factors is limited. We leveraged genetic data from genome-wide association studies (GWAS) and performed latent causal variable analyses using a hypothesis-free approach to infer causal associations between 1387 complex traits and ADHD. We identified 37 inferred potential causal associations with ADHD risk. Our results reveal that genetic variants associated with iron deficiency anemia (ICD10), obesity, type 2 diabetes, synovitis and tenosynovitis (ICD10), polyarthritis (ICD10), neck or shoulder pain, and substance use in adults display partial genetic causality on ADHD risk in children. Genetic variants associated with ADHD have a partial genetic causality increasing the risk for chronic obstructive pulmonary disease and carpal tunnel syndrome. Protective factors for ADHD risk included genetic variants associated with the likelihood of participating in socially supportive and interactive activities. Our results show that genetic liability to multiple complex traits influences a higher risk for ADHD, highlighting the potential role of cardiometabolic phenotypes and physical pain in ADHD’s aetiology. These findings have the potential to inform future clinical studies and development of interventions.

Background: Frontotemporal dementia (FTD) has a complex genetic aetiology, with mutations in several genes associated with different forms of the disease. However, the precise mechanisms underlying the selective vulnerability of the frontal and temporal brain regions remain unknown. Methods: We leveraged summary-based data from genome-wide association studies (GWASs) and performed LD-score regression to estimate pairwise genetic correlations between FTD risk and cortical brain imaging phenotypes. Then, we followed up strongly-correlated brain measures with GWAS-pairwise analyses to isolate specific genomic loci with a shared aetiology between FTD and brain structure. We also performed functional annotation and summary-based-data Mendelian randomisation for eQTL data for genes within the overlapping genomic loci of interest using human peripheral blood and brain tissue. We evaluated the gene expression in mice targeted brain regions to better understand the dynamics of the FTD candidate genes. Results: Pairwise genetic correlation estimates between FTD and brain morphology measures were high but not statistically significant. We identified five brain regions with a strong genetic correlation (rg > 0.45) with FTD risk. A genomic region in chromosome 17 was aetiologically shared between FTD, the right inferior parietal surface area, and the right medial orbitofrontal cortical thickness. Functional annotation identified eight protein-coding genes and NSF gene expression shared between FTD and variation in the two brain structure phenotypes. Building upon these findings, we show in a mouse model of FTD that cortical NSF expression decreases with age, corresponding closely with the steadily increasing burden of tau pathology in the cortex. Conclusions: Our results highlight the molecular and genetic overlap between brain morphology and higher risk for FTD, specifically for the right inferior parietal surface area and right medial orbitofrontal cortical thickness. In addition, our findings implicate NSF gene expression in the aetiology of FTD and elucidate how NSF expression changes uniquely contribute to risk for and the pathophysiology of frontotemporal lobar degeneration independent of its association with the MAPT locus.

Suicide is a major public health problem in Mexico and around the world. Genetic predisposition for major depressive disorder (MDD) has been associated with increased risk for suicidal behaviors (SB) in populations of European ancestry (EA). Here, we examine whether MDD polygenic risk scores (MDD PRS), derived from a genome-wide association study involving EA individuals, predict SB, including ideation, planning, and attempt, among Mexican youth using a longitudinal design. At baseline, participants (N = 1,128, 12-17 years, 55% women) were interviewed and genotyped as part of a general population survey on adolescent mental health. Eight years later, they were recontacted for a follow up visit (N = 437, 20-25 years, 63% women). At both assessments, individuals reported on their engagement in SB within the past year. MDD PRS were significantly positively associated with SB, particularly suicide ideation and planning during adolescence, accounting for ~4-5% of the variance in these outcomes. In contrast, associations between MDD PRS and SB during young adulthood did not reach statistical significance. Our results suggest that increased genetic liability for depression increased risk for SB, particularly during adolescence, expanding our knowledge of the genetic underpinnings of SB.

Pneumonia is a respiratory condition with complex etiology. Host genetic variation is thought to contribute to individual differences in susceptibility and symptom manifestation. Here, we analyze pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9980 cases and 86,519 controls) and perform a genomewide association study meta-analysis. We use gene-based tests, colocalization, genetic correlation, latent causal variable (LCV) and polygenic prediction in an independent Australian sample (N = 5595) to draw insights into the etiology of pneumonia risk. We identify two independent loci on chromosome 15 (lead single-nucleotide polymorphisms rs2009746 and rs76474922) to be associated with pneumonia (p < 5e−8). Gene-based tests revealed 18 genes in chromosomes 15, 16 and 9, including IL127, PBX3, ApoB receptor (APOBR) and smoking related genes CHRNA3/5, statistically associated with pneumonia. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. LCV analysis suggests a strong genetic causal relationship with cardiovascular health phenotypes. Polygenic risk scores for pneumonia significantly predicted self-reported pneumonia in an independent sample, albeit with a small effect size (OR = 1.11 95% CI [1.04, 1.19], p

In the present study, we sought to identify causal relationships between obesity and other complex traits and conditions using a data-driven hypothesis-free approach that uses genetic data to infer causal associations. We leveraged available summary-based genetic data from genome-wide association studies on 1498 phenotypes and applied the latent causal variable method (LCV) between obesity and all traits. We identified 110 traits causally associated with obesity. Of those, 109 were causal outcomes of obesity, while only leg pain in calves was a causal determinant of obesity. Causal outcomes of obesity included 26 phenotypes associated with cardiovascular diseases, 22 anthropometric measurements, nine with the musculoskeletal system, nine with behavioural or lifestyle factors including loneliness or isolation, six with respiratory diseases, five with body bioelectric impedances, four with psychiatric phenotypes, four related to the nervous system, four with disabilities or long-standing illness, three with the gastrointestinal system, three with use of analgesics, two with metabolic diseases, one with inflammatory response and one with the neurodevelopmental disorder ADHD, among others. In particular, some causal outcomes of obesity included hypertension, stroke, ever having a period of extreme irritability, low forced vital capacity and forced expiratory volume, diseases of the musculoskeletal system, diabetes, carpal tunnel syndrome, loneliness or isolation, high leukocyte count, and ADHD. Our results indicate that obesity causally affects a wide range of traits and comorbid diseases, thus providing an overview of the metabolic, physiological, and neuropsychiatric impact of obesity on human health.

Depression is one of the most common mental health disorders and one of the top causes of disability throughout the world. The present study sought to identify putative causal associations between depression and hundreds of complex human traits through a genome-wide screening of genetic data and a hypothesis-free approach. We leveraged genome-wide association studies summary statistics for depression and 1504 complex traits and investigated potential causal relationships using the latent causal variable method. We identified 559 traits genetically correlated with depression risk at FDR

Samples can be prone to ascertainment and attrition biases.The Australian Genetics of Depression Study is a large publicly recruited cohort (n=20,689) established to increase the understanding of depression and antidepressant treatment response. As part of the recruitment, participants donated a saliva sample and were given the option to consent to linkage of prescription records for research purposes. This study investigates differences between participants who donated a saliva sample or agreed to linkage of their records compared to those who did not. We observed that older, male participants with a higher education were more likely to donate a saliva sample. Self-reported bipolar disorder, ADHD, panic disorder, PTSD, substance use disorder and social anxiety disorder were associated with lower odds of donating a saliva sample whereas anorexia was associated with higher odds of donation. Male and younger participants showed higher odds of agreeing to record linkage. Participants with higher neuroticism scores and those with a history of bipolar disorder were also more likely to agree to record linkage whereas participants with a diagnosis of anorexia were less likely to agree. Increased likelihood of consent was also associated with increased genetic susceptibility to anorexia and reduced genetic risk for depression, and schizophrenia whereas there was no significant genetic effect for neuroticism. Overall, our results show moderate differences among these subsamples. Most current epidemiological studies do not adjust, nor search, for attrition biases at the genetic level. The possibility to do so is a strength of samples such as the AGDS. Our results suggest that analyses can be made more robust by identifying attrition biases both on the phenotypic and genetic level, and either contextualising them as a potential limitation or performing sensitivity analyses adjusting for them.

PurposeParkinson’s disease (PD) is a neurodegenerative disorder associated with progressive disability. While the precise aetiology is unknown, there is evidence of significant genetic and environmental influences on individual risk. The Australian Parkinson’s Genetics Study (APGS) seeks to study genetic and patient-reported data from a large cohort of individuals with PD in Australia to understand the sociodemographic, genetic, and environmental basis of PD susceptibility, symptoms and progression.ParticipantsIn the pilot phase reported here, 1,819 participants were recruited through assisted mailouts facilitated by Services Australia based on having three or more prescriptions for anti-PD medications in their Pharmaceutical Benefits Scheme (PBS) records. The average age at the time of the questionnaire was 64 ± 6 years. We collected patient-reported PD information and socio-demographic variables via an online (93% of the cohort) or paper-based (7%) questionnaire. One thousand five hundred thirty-two participants (84.2%) met all inclusion criteria, and 1,499 provided a DNA sample via traditional post.Findings to date65% of participants were male, and 92% identified as being of European descent. A previous traumatic brain injury was reported by 16% of participants and was correlated with a younger age of symptom onset. At the time of the questionnaire, constipation (36% of participants), depression (34%), anxiety (17%), melanoma (16%) and diabetes (10%) were the most reported comorbid conditions.Future plansWe plan to recruit sex- and age-matched unaffected controls, genotype all participants, and collect non-motor symptoms and cognitive function data. Future work will explore the role of genetic and environmental factors in the aetiology of PD susceptibility, onset, symptoms, and progression, including as part of international PD research consortia.Article summaryStrengths and limitations of this studyWe used a time- and cost-effective recruitment method that enabled us to reach out to a random sample of individuals who have been prescribed medications for Parkinson’s disease across all over Australia to invite them to participate in this study.The identities of letter recipients remained private and confidential and were not shared with the researchers. However, those recipients who were interested and willing to participate were directed to a website where they could sign up and provide informed consent.The source database only captures individuals who have been prescribed medications to treat Parkinson’s disease in Australia and who are eligible for Medicare. Those without an official diagnosis, not receiving treatment, or not eligible for government subsidies are not included.We collected a wide range of patient-reported variables relevant to disease onset, diagnosis, symptoms, medical comorbidities, lifestyle, and family history in a large cohort of participants. However, some variables might not be as accurate as when measured by a specialist clinician.Given the 9% response rate to our single-letter invitation, there is a substantial risk of self-selection bias. Thus, patient characteristics for this cohort might differ from those of the typical population of individuals with Parkinson’s disease in Australia.

Genome-wide association studies (GWAS) have identified genetic variants associated with brain morphology and substance use behaviors (SUB). However, the genetic overlap between brain structure and SUB has not been well characterized. We leveraged GWAS summary data of 71 brain imaging measures and alcohol, tobacco, and cannabis use to investigate their genetic overlap using linkage disequilibrium score regression. We used genomic structural equation modeling to model a “common SUB genetic factor” and investigated its genetic overlap with brain structure. Furthermore, we estimated SUB polygenic risk scores (PRS) and examined whether they predicted brain imaging traits using the Adolescent Behavior and Cognitive Development (ABCD) study. We identified 8 significant negative genetic correlations, including between (1) alcoholic drinks per week and average cortical thickness, and (2) intracranial volume with age of smoking initiation. We observed 5 positive genetic correlations, including those between (1) insula surface area and lifetime cannabis use, and (2) the common SUB genetic factor and pericalcarine surface area. SUB PRS were associated with brain structure variation in ABCD. Our findings highlight a shared genetic etiology between cortical brain morphology and SUB and suggest that genetic variants associated with SUB may be causally related to brain structure differences.

The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for their comorbidity in the Australian Genetics of Depression cohort study (N = 13,839). Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health. Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for 10 different antidepressants. Chronic pain was associated with an increased risk of depression (OR = 1.86 [1.37–2.54]), recent suicide attempt (OR = 1.88 [1.14–3.09]), higher use of tobacco (OR = 1.05 [1.02–1.09]) and misuse of painkillers (e.g., opioids; OR = 1.31 [1.06–1.62]). Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR = 0.75 [0.68–0.83]), escitalopram (OR = 0.75 [0.67–0.85]) and venlafaxine (OR = 0.78 [0.68–0.88]) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR = 0.45 [0.30–0.67]), escitalopram (OR = 0.45 [0.27–0.74]) and citalopram (OR = 0.32 [0.15–0.67]) specifically for chronic pain (among other indications) reported lower benefits compared to other participants taking these same medications but not for chronic pain. These findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further examination is warranted in targeted interventional clinical trials, which also include neuroimaging genetics and pharmacogenomics protocols. This work will advance the delineation of disease risk indicators and novel aetiological pathways for therapeutic intervention in comorbid pain and depression as well as other psychiatric comorbidities.

In the present study, we sought to identify causal relationships between obesity and other complex traits and conditions using a data-driven hypothesis-free approach that uses genetic data to infer causal associations.We leveraged available summary-based genetic data from genome-wide association studies on 1498 phenotypes and applied the latent causal variable method (LCV) between obesity and all traits.We identified 110 traits causally associated with obesity. Of those, 109 were causal outcomes of obesity, while only leg pain in calves was a causal determinant of obesity. Causal outcomes of obesity included 26 phenotypes associated with cardiovascular diseases, 22 anthropometric measurements, nine with the musculoskeletal system, nine with behavioural or lifestyle factors including loneliness or isolation, six with respiratory diseases, five with body bioelectric impedances, four with psychiatric phenotypes, four related to the nervous system, four with disabilities or long-standing illness, three with the gastrointestinal system, three with use of analgesics, two with metabolic diseases, one with inflammatory response and one with the neurodevelopmental disorder ADHD, among others. In particular, some causal outcomes of obesity included hypertension, stroke, ever having a period of extreme irritability, low forced vital capacity and forced expiratory volume, diseases of the musculoskeletal system, diabetes, carpal tunnel syndrome, loneliness or isolation, high leukocyte count, and ADHD.Our results indicate that obesity causally affects a wide range of traits and comorbid diseases, thus providing an overview of the metabolic, physiological, and neuropsychiatric impact of obesity on human health.

Study objectivePrevious neuroimaging studies have highlighted differences in white matter microstructure among individuals with different chronotypes, but it is unclear whether those differences are due to genetic or environmental factors.MethodsHere we leverage summary statistics from recent large-scale genome-wide association studies (GWAS) of chronotype and diffusion tensor imaging (DTI) measures to examine the genetic overlap and infer causal relationships between these traits.ResultsWe identified 29 significant pairwise genetic correlations, of which 13 also had evidence for a causal association. Negative genetic correlations were identified between chronotype and brain-wide mean, axial and radial diffusivities. When exploring individual tracts, ten negative genetic correlations were observed with mean diffusivities, 10 with axial diffusivities, 4 with radial diffusivities and 2 with mode of anisotropy. We found evidence for a possible causal association of chronotype with white matter microstructure in individual tracts including the posterior limb and retrolenticular part of the internal capsule; the genu and splenium of the corpus callosum and the posterior, superior and anterior regions of the corona radiata.ConclusionsOur results suggest that eveningness is associated with variation in tract-specific white matter microstructure and, for an evening person, increases in axial and / or radial diffusivities may influence a higher mean diffusivity. These findings add to our understanding of circadian preference and its relationship with the brain, providing new perspectives on the genetic neurological underpinnings of chronotype’s role in health and disease.Statement of SignificanceSleep is essential for a healthy brain function, particularly for neural organization and brain structure development. Individual chronotype differences have been associated with depression, schizophrenia, diabetes and obesity, among other conditions. Investigating the shared genetic aetiology between chronotype and white matter microstructure is essential to understand the neurological basis of individual variation in chronotype. In the present study, we show that tract-specific white matter microstructure is genetically correlated and causally associated with chronotype.

BackgroundSleep apnoea is characterised by periods of halted breathing during sleep. Despite its association with severe health conditions, the aetiology of sleep apnoea remains understudied, and previous genetic analyses have not identified many robustly associated genetic risk variants.MethodsWe performed a genome-wide association study (GWAS) meta-analysis of sleep apnoea across five cohorts (NTotal=523,366), followed by a multi-trait analysis of GWAS (MTAG) to boost power, leveraging the high genetic correlation between sleep apnoea and snoring. We then adjusted our results for the genetic effects of body mass index (BMI) using multi-trait-based conditional & joint analysis (mtCOJO) and sought replication of lead hits in a large cohort of participants from 23andMe, Inc (NTotal=1,477,352; Ncases=175,522). We also explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method.ResultsOur MTAG analysis uncovered 49 significant independent loci associated with sleep apnoea risk. Twenty-nine variants were replicated in the 23andMe cohort. We observed genetic correlations with several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-associated conditions.ConclusionsOur study uncovered multiple genetic loci associated with sleep apnoea risk, thus increasing our understanding of the aetiology of this condition and its relationship with other complex traits.

Study ObjectiveSleep is essential for both physical and mental health, and there is a growing interest in understanding how different factors shape individual variation in sleep duration, quality and patterns, or confer risk for sleep disorders. The present study aimed to identify novel inferred causal relationships between sleep-related traits and other phenotypes, using a genetics-driven hypothesis-free approach not requiring longitudinal data.MethodsWe used summary-level statistics from genome-wide association studies and the latent causal variable (LCV) method to screen the phenome and infer causal relationships between seven sleep-related traits (insomnia, daytime dozing, easiness of getting up in the morning, snoring, sleep duration, napping, and morningness) and 1,527 other phenotypes.ResultsWe identify 84 inferred causal relationships. Among other findings, connective tissue disorders increase insomnia risk and reduce sleep duration; depression-related traits increase insomnia and daytime dozing; insomnia, napping, and snoring are affected by obesity and cardiometabolic traits and diseases; and working with asbestos, thinner, or glues may increase insomnia risk, possibly through an increased risk of respiratory disease or socio-economic related factors.ConclusionOverall, our results indicate that changes in sleep variables are predominantly the consequence, rather than the cause, of other underlying phenotypes and diseases. These insights could inform the design of future epidemiological and interventional studies in sleep medicine and research.

RationalePneumonia is a respiratory condition with complex aetiology. Host genetic variation is thought to contribute to individual differences in susceptibility and symptom manifestation.MethodsWe analysed pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9,980 cases and 86,519 controls). We perform genome-wide association study (GWAS) meta-analysis, gene-based test, colocalisation, genetic correlation, latent causal variable and polygenic prediction in an independent Australian sample (N=5,595) to draw insights into the genetic aetiology of pneumonia risk.ResultsWe identify two independent loci on chromosome 15 (lead SNPs rs2009746 and rs76474922) to be associated with pneumonia(pIL127, PBX3, APOBRand smoking related genesCHRNA3/5, associated with pneumonia. Evidence ofHYKKandPBX3involvement in pneumonia risk was supported by eQTL colocalisation analysis. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. Latent causal variable analysis suggests a strong genetic causal relationship cardiovascular health phenotypes and pneumonia risk. Polygenic risk scores (PRS) for pneumonia significantly predicted self-reported pneumonia history in an independent Australian sample, albeit with a small effect size (OR=1.11 95%CI=[1.04-1.19], pConclusionsAltogether, our results highlight common genetic variants, genes and potential pathways that contribute to individual differences in susceptibility to pneumonia, and advance our understanding of the genetic factors underlying heterogeneity in respiratory medical outcomes.

SUMMARY Background The bidirectional relationship between depression and chronic pain is well recognized but their clinical management remains challenging. Here we characterize the shared aetiology and risk factors for their comorbidity using large population cohorts to advance understanding of pharmacological treatment outcomes. Methods Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health (N=13,839). Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for 10 different antidepressants. Findings Chronic pain was associated with an increased risk of depression (OR=1.86 [1.37–2.54]), recent suicide attempt (OR=1.88[1.14–3.09]), higher use of alcohol, tobacco and painkiller misuse. Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR=0.75[0.68–0.83]), escitalopram (OR=0.75[0.67–0.85]) and venlafaxine (OR=0.78[0.68–0.88]) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR=0.45[0.30–0.67]), escitalopram (OR=0.45[0.27–0.74]) and citalopram (OR=0.32[0.15–0.67]) specifically for chronic pain reported lower benefits compared to other participants taking these same medications but not for chronic pain. Interpretation The findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further assessment is warranted in targeted interventional trials. This approach will advance precision psychiatry and assist in clinical management by choosing the most suitable treatment for patients, informed by specific symptoms and comorbidities. Funding source Data collection for the Australian Genetics of Depression Study was possible thanks to funding from the Australian National Health and Medical Research Council (NHMRC) to NGM (GNT1086683); data collection for the Prospective Imaging Study of Ageing: Genes, Brain and Behaviour was possible thanks to an NHMRC Dementia Research Team Grant administered by QIMR Berghofer Medical Research Institute (GNT1095227). The research funders did not participate in the study design, data analyses, results interpretation or writing of the manuscript.

Study ObjectiveSleep is essential for both physical and mental health. There is an increasing interest in understanding how different factors shape individual variation in sleep duration, quality and patterns, or confer risk for sleep disorders. The present study aimed to identify novel causal relationships between sleep-related traits and other phenotypes, using a genetics-driven hypothesis-free approach not requiring longitudinal data.MethodsWe used genetic data and the latent causal variable (LCV) method to screen the phenome and infer causal relationships between seven sleep-related traits (insomnia, daytime dozing, easiness of getting up in the morning, snoring, sleep duration, napping, and morningness) and 1,527 different phenotypes.ResultsWe identify 84 significant causal relationships. Among other findings, poor health of musculoskeletal and connective tissue disorders increase insomnia risk and reduce sleep duration; depression-related traits increase insomnia and daytime dozing; insomnia, napping and snoring are affected by obesity and cardiometabolic traits and diseases; and working with asbestos, thinner, or glues increases insomnia, potentially through an increased risk of respiratory disease.ConclusionOverall, our results indicate that changes in sleep variables are predominantly the consequence, rather than the cause, of other underlying phenotypes and diseases. These insights could inform the design of future epidemiological and interventional studies in sleep medicine and research.

We conducted the largest study of snoring using data from the UK Biobank (n∼ 408,000; snorers ∼152,000). A genome-wide association study (GWAS) identified 42 genome-wide significant loci, with a SNP-based heritability estimate of ∼10% on the liability scale. Genetic correlations with body mass index, alcohol intake, smoking, schizophrenia, anorexia nervosa and neuroticism were observed. Gene-based associations identified 173 genes, includingDLEU7, MSRB3andPOC5highlighting genes expressed in brain, cerebellum, lungs, blood, and oesophagus tissues. We used polygenic scores (PGS) to predict recent snoring and probable obstructive sleep apnoea (OSA) in an independent Australian sample (n∼8,000). Mendelian randomisation analyses provided evidence that larger whole body fat mass causes snoring. Altogether, our results uncover new insights into the aetiology of snoring as a complex sleep-related trait and its role in health and disease beyond being a cardinal symptom of OSA.

Resumen Objetivo Determinar si la informacion terapeutica escrita de calidad, frente a la informacion escrita estandar, incrementa la satisfaccion con el servicio de fisioterapia durante la estancia hospitalaria de intervenidos quirurgicamente por fractura de cadera. Material y metodo Estudio de diseno experimental, aleatorizado, con grupo control, desarrollado en el servicio de fisioterapia del Hospital Neurotraumatologico de Jaen. Se reclutaron 48 pacientes que cumplian los siguientes criterios de inclusion: mayor de edad, intervenido quirurgicamente de fractura de cadera y adecuado nivel de alfabetizacion. Se perdieron 10 sujetos durante el seguimiento. Se aleatorizo la inclusion a 2 grupos: experimental (n = 18) y control (n = 20). Ambos grupos recibieron tratamiento estandarizado de fisioterapia. El grupo control recibio un panfleto con informacion estandar y el grupo experimental recibio un nuevo modelo que cumplia criterios de calidad: legibilidad, validado por 10 expertos y sometido al cuestionario Ensuring Quality Information for Patients (EQIP). En ambos grupos se midieron las variables: numero de sesiones, duracion de sesion, capacidad para caminar, dolor, indice de Barthel (inicio-final) y satisfaccion con el servicio de fisioterapia (cuestionario MedRisk). Resultados El tratamiento de fisioterapia fue efectivo en ambos grupos: disminucion significativa del dolor y mejora de la discapacidad (p Conclusiones La informacion terapeutica escrita de calidad contribuye a mejorar la satisfaccion del paciente con el servicio de fisioterapia.

In this article, we describe the MIRI Imager module (MIRIM), which provides broad-band imaging in the 5 - 27 microns wavelength range for the James Webb Space Telescope. The imager has a 0"11 pixel scale and a total unobstructed view of 74"x113". The remainder of its nominal 113"x113" field is occupied by the coronagraphs and the low resolution spectrometer. We present the instrument optical and mechanical design. We show that the test data, as measured during the test campaigns undertaken at CEA-Saclay, at the Rutherford Appleton Laboratory, and at the NASA Goddard Space Flight Center, indicate that the instrument complies with its design requirements and goals. We also discuss the operational requirements (multiple dithers and exposures) needed for optimal scientific utilization of the MIRIM., Comment: 29 pages, 9 figures

The discovery of the M-sigma relation, the local galaxy bimodality, and the link between black-hole and host-galaxy properties, have raised the question whether AGN play a role in galaxy evolution. Several theoretical models implement AGN feedback to explain the observed galaxy luminosity function, and possibly the color and morphological transformation of spiral galaxies into passive ellipticals. To understand the importance of AGN feedback, a study of the AGN populations in the radio-optical domain is crucial. A mass sequence linking star-forming galaxies and AGN has been already noted in previous works, and it is now investigated as possible evolutionary sequence. We observed a sample of 119 intermediate-redshift (0.04, Comment: 20 pages, 19 figures, accepted for publication in A&A

Sagittarius A*, the super-massive black hole at the center of the Milky Way, is surrounded by a small cluster of high velocity stars, known as the S-stars. We aim to constrain the amount and nature of stellar and dark mass associated with the cluster in the immediate vicinity of Sagittarius A*. We use near-infrared imaging to determine the $K_\mathrm{s}$-band luminosity function of the S-star cluster members, and the distribution of the diffuse background emission and the stellar number density counts around the central black hole. This allows us to determine the stellar light and mass contribution expected from the faint members of the cluster. We then use post-Newtonian N-body techniques to investigate the effect of stellar perturbations on the motion of S2, as a means of detecting the number and masses of the perturbers. We find that the stellar mass derived from the $K_\mathrm{s}$-band luminosity extrapolation is much smaller than the amount of mass that might be present considering the uncertainties in the orbital motion of the star S2. Also the amount of light from the fainter S-cluster members is below the amount of residual light at the position of the S-star cluster after removing the bright cluster members. If the distribution of stars and stellar remnants is strongly enough peaked near Sagittarius A*, observed changes in the orbital elements of S2 can be used to constrain both their masses and numbers. Based on simulations of the cluster of high velocity stars we find that at a wavelength of 2.2 $\mu$m close to the confusion level for 8 m class telescopes blend stars will occur (preferentially near the position of Sagittarius A*) that last for typically 3 years before they dissolve due to proper motions., Comment: 14 pages, 11 figures, minor changes to match the published version in Astronomy & Astrophysics

The Verification Model (VM) of MIRI has recently completed an extensive programme of cryogenic testing, with the Flight Model (FM) now being assembled and made ready to begin performance testing in the next few months. By combining those VM test results which relate to MIRI's scientific performance with measurements made on FM components and sub-assemblies, we have been able to refine and develop the existing model of the instrument's throughput and sensitivity. We present the main components of the model, its correlation with the existing test results and its predictions for MIRI's performance on orbit.

We are using integral field spectroscopy (IFS) data together with archival Hubble Space Telescope (HST) images, for carrying out a program aimed at studying a representative sample of local luminous and ultraluminous infrared galaxies (LIRGs and ULIRGs; 11 ≤ log(LIR/L⊙)≤13). Our goals are to characterize the stellar and ionized gas structure, the two dimensional extinction and star formation, the kinematical properties and the dynamical mass tracers. Here we will review some of the most interesting results obtained from our sample, including detailed studies for some individual galaxies. The implications for deriving the star formation rate (SFR) and mass when studying high-redshift galaxies will be briefly discussed too.

We present the first realistic simulations of how high-redshift star forming galaxies will be observed by MIRI (Mid IR Instrument). The simulations presented have been developed using the new tool Specsim, and are part of an ongoing project aimed at studying a representative sample of Ultraluminous Infrared Galaxies (ULIRGs) with integral field spectroscopy (IFS) data.

The Near Infrared Spectrograph (NIRSpec) on board of the James Webb Space Telescope (JWST) will be equipped with an Integral Field Unit (IFU) which will allow the two-dimensional spectral characterization of astronomical objects with unprecedented depths, especially in the 2-5 micron wavelength range. In particular, NIRSpec-IFU observations of high-z galaxy populations will permit the capture of their often complex two-dimensional physical and kinematical structure, a pre-requisite for carrying out a number of studies. These types of observations will also help to understand possible observational biases of large 1D (i.e. slit) surveys to be carried out in multi-object mode. Here we describe the main characteristics of the NIRSpec-IFU, as well as its expected sensitivity and performance for observations of high-z galaxy populations.

We report on the results of new simulations of near-infrared (NIR) observations of the Sagittarius A* (Sgr A*) counterpart associated with the super-massive black hole at the Galactic Center. The observations have been carried out using the NACO adaptive optics (AO) instrument at the European Southern Observatory's Very Large Telescope and CIAO NIR camera on the Subaru telescope (13 June 2004, 30 July 2005, 1 June 2006, 15 May 2007, 17 May 2007 and 28 May 2008). We used a model of synchrotron emission from relativistic electrons in the inner parts of an accretion disk. The relativistic simulations have been carried out using the Karas-Yaqoob (KY) ray-tracing code. We probe the existence of a correlation between the modulations of the observed flux density light curves and changes in polarimetric data. Furthermore, we confirm that the same correlation is also predicted by the hot spot model. Correlations between intensity and polarimetric parameters of the observed light curves as well as a comparison of predicted and observed light curve features through a pattern recognition algorithm result in the detection of a signature of orbiting matter under the influence of strong gravity. This pattern is detected statistically significant against randomly polarized red noise. Expected results from future observations of VLT interferometry like GRAVITY experiment are also discussed., Comment: 26 pages, 38 figures, accepted for publication by A&A

Context. Small star-forming galaxies made out of collisional debris have been found in a variety of merging systems. So far only a few of them are known in Ultraluminous Infrared Galaxies (ULIRGs) although they show clear signs of interactions. Whether external star formation may take place in such objects in an open question. Aims. The aim of this paper is to identify and characterise the physical and kinematic properties of the external star-forming regions in a sample of ULIRGs, including Tidal Dwarf Galaxies (TDG) candidates. The likelihood of survival of these regions as TDGs is also evaluated. Methods. The analysis is based on optical Integral Field Spectroscopy (IFS) and high angular resolution Hubble Space Telescope (HST) imaging. Results. We found that the presence of external star-forming regions is common, with 12 objects being identified in 5 ULIRGs. These regions show a large range of dynamical mass up to 1 x 1010 M⊙, with average sizes of ∼750 pc. In addition, the line ratios (HII region-like), metallicities (12 + log (O/H) ∼ 8,6) and Ha equivalent widths (34-257 Å) are typical of young bursts of star formation (age ∼ 5-8 Myr), and similar to those of the TDG candidates found in less luminous mergers and compact groups of galaxies. The extinction corrected Hα luminosity of these young bursts leads to masses for the young stellar component of ∼2 × 106-7 × 108 M⊙. The likelihood of survival of these regions as TDGs is discussed based on their structural and kinematic properties. Particularly interesting is our finding that most of these systems follow the relation between effective radius and velocity dispersion found at lower (globular clusters) and higher (Elliptical) mass systems, which suggests they are stable against internal motions. The stability against forces from the parent galaxy is studied on the basis of several criteria and a comparison of the data with the predictions of dynamical evolutionary models is also performed. Five regions out of twelve show High-Medium or High likelihood of survival based on all the utilised tracers. Our best candidate, which satisfies all criteria, is located in the advanced merger IRAS 15250+3609 and presents a velocity field decoupled from the relatively distant parent galaxy. © ESO 2007., Financial support was provided by the Spanish Ministry for Education and Science through grant AYA2002-01055

NGC 3718 is a low-ionization nuclear emission line region (LINER) L 1.9 galaxy, lying at a distance of about ~17.4 Mpc from the Earth; its similarities with NGC 5128 often award it the name northern Centaurus A. The presence of a compact radio source with a candidate jet structure, a prominent dust lane, and a strongly warped molecular and atomic gas disk are indications that NGC 3718 has undergone some sort of a large-scale gravitational interaction sometime in the recent past, which channeled gas towards the center, feeding the black hole and igniting the central engine. One proposed scenario involves an encounter with the close neighboring galaxy NGC 3729, while other authors favor a merging event with mass ratio ≥(3−4):1 as the origin of NGC3718. We use high angular resolution (~100 mas) e-Merlin radio and Subaru near-IR (NIR) (~170 mas) data to take a detailed view of the processes taking place in its central region. In order to preserve some objectivity in our interpretation, we combine our results with literature values and findings from previous studies. Our NIR maps suggest, on the one hand, that towards the stellar bulge there are no large-scale absorption phenomena caused by the apparent dust lane and, on the other, that there is a significant (local) contribution from hot (~1000 K) dust to the nuclear NIR emission. The position where this takes place appears to be closer to the offset compact radio emission from our e-Merlin 6 cm map and is offset by ~4.25 pc from the center of the underlying stellar bulge. The shape of the radio map suggests the presence of one (or possibly two, forming an X-shape) bipolar structure(s) ~1 (~0.6) arcsec across, which combined with the balance between the gas and the stellar velocity dispersions and the presence of hard X-ray emission, point towards effects expected by AGN feedback. We also argue that NGC 3718 has a core in its surface brightness profile, although it is a gas-rich galaxy and we discuss its mixed photometric and spectroscopic characteristics. These characteristics combined with the observed spatial NIR and radio emission offsets, the relative redshift between the broad and the narrow Hα line, the limited star formation activity, and AGN feedback strongly imply the existence of a supermassive black hole recoil. Finally, we discuss a possible interpretation that could naturally incorporate all these findings into one physically consistent picture.

MIRI, the Mid-InfraRed Instrument, is one of four instruments being built for the James Webb Space Telescope, and is developed jointly between an EuropeanConsortium and the US. In this paper we present a software data simulator for one of MIRI's four instruments: the Integral Field Unit (IFU) Medium Resolution Spectrometer (MIRI-MRS), the first mid-infrared IFU spectrograph, and one of the first IFUs to be used in a space mission. To give the MIRI community a preview of the properties of the MIRI-MRS data products before the telescope is operational, the Specsim tool has been developed to model, in software, the operation of the spectrometer. Specsim generates synthetic data frames approximating those which will be taken by the instrument in orbit. The program models astronomical sources and generates detector frames using the predicted and measured optical properties of the telescope and MIRI. These frames can then be used to illustrate and inform a range of operational activities, including data calibration strategies and the development and testing of the data reduction software for the MIRI-MRS. Specsim will serve as a means of communication between the many consortium members by providing a way to easily illustrate the performance of the spectrometer under different circumstances, tolerances of components and design scenarios., Comment: 8 pages, 5 figures; A high resolution version is available at http://www.roe.ac.uk/~npfl/Publications/lgw+06.ps.gz (Changed URL of high-res version)

The luminous infrared galaxy Arp 299 (IC 694 + NGC 3690) is studied using optical integral field spectroscopy obtained with the INTEGRAL system, together with archival Hubble Space Telescope WFPC2 and NICMOS images. The stellar and ionized gas morphology shows λ-dependent variations due to the combined effects of the dust internal extinction and the nature and spatial distribution of the different ionizing sources. The two-dimensional ionization maps have revealed an off-nuclear conical structure of about 4 kpc in length, characterized by high-excitation conditions and a radial gradient in the gas electron density. The apex of this structure coincides with B 1 region of NGC 3690, which in turn presents Seyfert-like ionization, high extinction, and a high velocity dispersion. These results strongly support the hypothesis that B1 is the true nucleus of NGC 3690, where an AGN is located. In the circumnuclear regions H II-like ionization dominates, while LINER-like ionization is found elsewhere. The Hα-emitting sources with ages from 3.3 to 7.2 × 106 yr, have masses of between 6 and 680 × 106 M⊙; and contribute about 45% to the bolometric luminosity (extinction corrected). The ionized (Hα) and neutral (Na D) gas velocity fields show similar structure on scales of several hundred to about 1 kpc, indicating that these gas components are kinematically coupled. The kinematic structure is complex and on scales of about 0.2 kpc does not appear to be dominated by the presence of ordered, rotational motions. The large velocity dispersion measured in NGC 3690 indicates that this galaxy is the most massive of the system. The low velocity amplitude and dispersion of the interface suggest that the ionized gas is slowly rotating or in a close to quiescent phase. © 2006. The American Astronomical Society. All rights reserved., This work has been supported by the Spanish Ministerio de Educación y Ciencia, under grant BES2003-0852, projects AYA2002-01055 and ESP2005-01480.

Integral field optical fiber spectroscopy obtained with the INTEGRAL system, together with archival HST (WFPC2 and NICMOS) images, is used to carry out a program aimed at studying the internal physical structure and kinematics of a representative sample of Ultraluminous Infrared Galaxies (ULIRGs). Our goals are to characterize each individual system in order to infer generic properties of ULIRGs, and to perform simulations of high-redshift galaxy observations with JWST instruments. This work will be useful for stablishing connections between local ULIRGs and high-z galaxies, such as sub-mm galaxies, Lyman break galaxies and Spitzer galaxies. Here, we present results related to the kinematic properties of these systems, and the implications when deriving dynamical masses of high-redshift galaxies. Some results for IRAS 16007+3743 are shown too.