History of childhood maltreatment associated with hospitalization or death due to COVID-19: a cohort study.

BACKGROUND: Childhood maltreatment (CM) has been indicated in adverse health outcomes across the lifespan, including severe infection-related outcomes. Yet, data are scarce on the potential role of CM in severe COVID-19-related outcomes as well as on mechanisms underlying this association. METHODS: We included 151,427 individuals in the UK Biobank who responded to questions on the history of CM in 2016 and 2017 and were alive on January 31, 2020. Binomial logistic regression models were performed to estimate the association between a history of CM and severe COVID-19 outcomes (i.e. hospitalization or death due to COVID-19), as well as COVID-19 diagnosis and vaccination as secondary outcomes. We then explored the potential mediating roles of socio-economic status, lifestyle and pre-pandemic comorbidities, and the effect modification by polygenic risk score for severe COVID-19 outcomes. RESULTS: The mean age of the study population at the start of the pandemic was 67.7 (SD = 7.72) years, and 56.5% were female. We found the number of CM types was associated with the risk of severe COVID-19 outcomes in a graded manner (pfor trend < 0.01). Compared to individuals with no history of CM, individuals exposed to any CM were more likely to be hospitalized or die due to COVID-19 (odds ratio [OR] = 1.54 [95%CI 1.31-1.81]), particularly after physical neglect (2.04 [1.57-2.62]). Largely comparable risk patterns were observed across groups of high vs. low genetic risks for severe COVID-19 outcomes (pfor difference > 0.05). Mediation analysis revealed that 50.9% of the association between CM and severe COVID-19 outcomes was explained by suboptimal socio-economic status, lifestyle, and pre-pandemic diagnosis of psychiatric disorders or other chronic medical conditions. In contrast, any CM exposure was only weakly associated with COVID-19 diagnosis (1.06 [1.01-1.12]) while significantly associated with not being vaccinated for COVID-19 (1.21 [1.13-1.29]). CONCLUSIONS: Our results add to the growing knowledge base indicating the role of childhood maltreatment in negative health outcomes across the lifespan, including severe COVID-19-related outcomes. The identified factors underlying this association represent potential intervention targets for mitigating the harmful effects of childhood maltreatment in COVID-19 and similar future pandemics.

Adverse childhood experiences and psychological functioning among women with schizophrenia or bipolar disorder: population-based study.

BACKGROUND: Adverse childhood experiences (ACEs) are well-known risk factors for schizophrenia and bipolar disorder. AIMS: The aim was to study the associations between specific ACEs and psychological functioning in women with schizophrenia or bipolar disorder. METHOD: Among 29 367 women (mean age 44 years) from the Icelandic Stress-And-Gene-Analysis (SAGA) study, 534 (1.8%, mean age 40) reported having been diagnosed with schizophrenia or bipolar disorder, which were combined to 'severe mental disorders'. Participants reported on 13 types of ACEs, childhood deprivation and psychological functioning (defined as coping ability and current symptoms of depression, anxiety and sleep disturbances). Adjusted Poisson regression calculated prevalence ratios (PRs) between ACEs and severe mental disorders. Linear regression assessed the association between ACEs and psychological functioning among women with a severe mental disorder. RESULTS: Women with a severe mental disorder reported more ACEs (mean 4.57, s.d. = 2.82) than women without (mean 2.51, s.d. = 2.34) in a dose-dependent manner (fully-adjusted PR = 1.23 per ACE, 95% CI 1.20-1.27). After mutual adjustment for other ACEs, emotional abuse, sexual abuse, mental illness of a household member, emotional neglect, bullying and collective violence were associated with severe mental disorders. Among women with severe mental disorders, a higher number of ACEs was associated with increased symptom burden of depression (ß = 2.79, 95% CI = 1.19-4.38) and anxiety (ß = 2.04, 95% CI = 0.99-3.09) including poorer sleep quality (ß = 0.83, 95% CI = 0.07-1.59). Findings were similar for schizophrenia and bipolar disorder separately. CONCLUSION: Women with schizophrenia or bipolar disorder show a strong history of ACEs, which may interfere with their psychological functioning and, therefore, need to be addressed as part of their treatment, for example, with trauma-focused psychotherapy.

Trends of perceived disruption in healthcare services during the pandemic: findings from the COVID-19 National Resilience Cohort in Iceland.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused major disruptions in healthcare services worldwide. Yet, little is known about the association between perceived disruption in healthcare services and socio-demographic factors, pre-existing health conditions as well as concurrent physical and psychological symptoms. METHODS: Leveraging data from the Icelandic COVID-19 National Resilience Cohort, we performed a repeated measure analysis among 15 754 participants who responded to the question on perceived disruption in healthcare services from December 2020 to July 2021, to explore its association with socio-demographic factors, health indicators and conditions. Furthermore, we performed a longitudinal analysis among 7848 participants with two repeated measures to explore the association between timing and duration of perceived disruption in healthcare services and changes in depression, anxiety, sleep quality and somatic symptoms. RESULTS: The prevalence of perceived disruption in healthcare services slightly decreased over time (P < 0.01). Perceived disruption in healthcare services was more prevalent among individuals with pre-existing health conditions, i.e. history of psychiatric disorders (prevalence ratio = 1.59, 95% confidence interval 1.48-1.72) and chronic somatic conditions [1.40 (1.30-1.52)]. However, no increase in the prevalence of perceived disruption in healthcare services was observed among individuals diagnosed with COVID-19 [0.99 (0.84-1.18)]. Moreover, we found that emerging perceived disruption in healthcare services was associated with an increase in symptoms of mental illness during the pandemic (ßs 0.06-0.68). CONCLUSIONS: A disruption in healthcare services during the COVID-19 pandemic was reported by vulnerable groups, while the Icelandic healthcare system managed to maintain accessible services to individuals with COVID-19.

Association between adverse childhood experiences and perinatal depressive symptoms: a cross-sectional analysis of 16,831 women in Iceland.

Emerging data suggest that certain adverse childhood experiences (ACEs) are associated with perinatal depression (PND). However, few studies have comprehensively assessed the cumulative number and types of ACEs and their association to PND. We conducted a cross-sectional analysis among 16,831 female participants from the Stress-And-Gene-Analysis (SAGA) cohort in Iceland, 2018. ACEs were surveyed with the World Health Organization ACE-International questionnaire, while PND symptoms were assessed using the Edinburgh Postnatal Depression Scale (lifetime version). We, while adjusting for confounding factors, estimated the prevalence ratio (PR) of PND in relation to total number of ACEs using the Poisson quasi-likelihood model and further performed analyses for type-specific ACEs. At a mean age of 44 years (SD ± 11.1), 6,201 (36.8%) participants had experienced probable PND. Total number of ACEs was positively associated with PND (PR 1.11 per ACE, 95% CI: 1.10-1.11), also among women without any psychiatric comorbidities (PR 1.13, 95% CI: 1.11-1.14). PRs increased in a dose-response manner with the number of ACEs (P for trend < 0.001); women that endorsed 5 or more ACEs were twice as likely to have experienced PND (PR 2.24, 95% CI: 2.09-2.41). All ACE types (n = 13) were associated with PND, with most pronounced association for emotional neglect by a guardian (PR 1.53, 95% CI: 1.47-1.59). Our findings suggest a positive association between number of ACEs and PND symptoms. If our results are confirmed with prospective data, healthcare providers need to be alert of the risk of PND among expecting mothers with history of ACEs.

Association between adverse childhood experiences and premenstrual disorders: a cross-sectional analysis of 11,973 women.

BACKGROUND: Childhood abuse and neglect have been associated with premenstrual disorders (PMDs), including premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). However, the associations of other adverse childhood experiences (ACEs) and the cumulative number of ACEs with PMDs remain to be explored. METHODS: To evaluate the associations of the cumulative number and types of ACEs with PMDs, we conducted a cross-sectional analysis with a subsample of menstruating women within the Stress-And-Gene-Analysis (SAGA) cohort, assessed for PMDs and ACEs (N=11,973). The cumulative and individual exposure of 13 types of ACEs was evaluated by a modified ACE-International Questionnaire. A modified version of the Premenstrual Symptom Screening Tool was used to identify probable cases of PMDs, further sub-grouped into PMS and PMDD. Prevalence ratios (PRs) of PMDs in relation to varying ACEs were estimated using Poisson regression. RESULTS: At a mean age of 34.0 years (standard deviation (SD) 9.1), 3235 (27%) met the criteria of probable PMDs, including 2501 (21%) for PMS and 734 (6%) for PMDD. The number of ACEs was linearly associated with PMDs (fully-adjusted PR 1.12 per ACE, 95% CI 1.11-1.13). Specifically, the PR for PMDs was 2.46 (95% CI 2.21-2.74) for women with 4 or more ACEs compared with women with no ACEs. A stronger association was observed for probable PMDD compared to PMS (p for difference <0.001). The associations between ACEs and PMDs were stronger among women without PTSD, anxiety, or depression, and without childhood deprivation and were stronger among women a lower level of social support (p for interaction<0.001). All types of ACEs were positively associated with PMDs (PRs ranged from 1.11 to 1.51); the associations of sexual abuse, emotional neglect, family violence, mental illness of a household member, and peer and collective violence were independent of other ACEs. CONCLUSIONS: Our findings suggest that childhood adverse experiences are associated with PMDs in a dose-dependent manner. If confirmed by prospective data, our findings support the importance of early intervention for girls exposed to ACEs to minimize risks of PMDs and other morbidities in adulthood.

Cesarean birth, obstetric emergencies, and adverse neonatal outcomes in Iceland during a period of increasing labor induction.

BACKGROUND: The rate of labor induction has risen steeply throughout the world. This project aimed to estimate changes in the rates of adverse maternal and neonatal outcomes in Iceland between 1997 and 2018, and to assess whether the changes can be explained by an increased rate of labor induction. METHODS: Singleton live births, occurring between 1997 and 2018, that did not start by prelabor cesarean, were identified from the Icelandic Medical Birth Register (n = 85 971). Rates of intrapartum cesarean birth (CB), obstetric emergencies, and neonatal outcomes were calculated, and adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) were estimated with log-binomial regression (reference: 1997-2001). Adjustments were made for: (a) maternal characteristics, and (b) labor induction and gestational age. RESULTS: The rate of labor induction increased from 13.6% in the period 1997-2001 to 28.1% in the period 2014-2018. The rate of intrapartum CB decreased between the periods of 1997-2001 and 2014-2018 for both primiparous (aRR 0.76, 95% CI: 0.69 to 0.84) and multiparous women (aRR 0.55, 95% CI: 0.49 to 0.63). The rate of obstetric emergencies and adverse neonatal outcomes also decreased between these time periods. Adjusting for labor induction did not attenuate these associations. CONCLUSIONS: The rates of adverse maternal outcomes and adverse neonatal outcomes decreased over the study period. However, there was no evidence that this decrease could be explained by the increased rate of labor induction.

Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the ß-amyloid cascade.

G-STRATEGY: Optimal Selection of Individuals for Sequencing in Genetic Association Studies.

In a large-scale genetic association study, the number of phenotyped individuals available for sequencing may, in some cases, be greater than the study's sequencing budget will allow. In that case, it can be important to prioritize individuals for sequencing in a way that optimizes power for association with the trait. Suppose a cohort of phenotyped individuals is available, with some subset of them possibly already sequenced, and one wants to choose an additional fixed-size subset of individuals to sequence in such a way that the power to detect association is maximized. When the phenotyped sample includes related individuals, power for association can be gained by including partial information, such as phenotype data of ungenotyped relatives, in the analysis, and this should be taken into account when assessing whom to sequence. We propose G-STRATEGY, which uses simulated annealing to choose a subset of individuals for sequencing that maximizes the expected power for association. In simulations, G-STRATEGY performs extremely well for a range of complex disease models and outperforms other strategies with, in many cases, relative power increases of 20-40% over the next best strategy, while maintaining correct type 1 error. G-STRATEGY is computationally feasible even for large datasets and complex pedigrees. We apply G-STRATEGY to data on high-density lipoprotein and low-density lipoprotein from the AGES-Reykjavik and REFINE-Reykjavik studies, in which G-STRATEGY is able to closely approximate the power of sequencing the full sample by selecting for sequencing a only small subset of the individuals.

Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

MASTOR: mixed-model association mapping of quantitative traits in samples with related individuals.

Genetic association studies often sample individuals with known familial relationships in addition to unrelated individuals, and it is common for some individuals to have missing data (phenotypes, genotypes, or covariates). When some individuals in a sample are related, power can be gained by incorporating all individuals in the analysis, including individuals with partially missing data, while properly accounting for the dependence among them. We propose MASTOR, a mixed-model, retrospective score test for genetic association with a quantitative trait. MASTOR achieves high power in samples that contain related individuals by making full use of the relationship information to incorporate partially missing data in the analysis while correcting for dependence. Individuals with available phenotype and covariate information who are not genotyped but have genotyped relatives in the sample can still contribute to the association analysis because of the dependence among genotypes. Similarly, individuals who are genotyped but are missing covariate or phenotype information can contribute to the analysis. MASTOR is valid even when the phenotype model is misspecified and with either random or phenotype-based ascertainment. In simulations, we demonstrate the correct type 1 error of MASTOR, the increase in power that comes from making full use of the relationship information, the robustness to misspecification of the phenotype model, and the improvement in power that comes from modeling the heritability. We show that MASTOR is computationally feasible and practical in genome-wide association studies. We apply MASTOR to data on high-density lipoprotein cholesterol from the Framingham Heart study.

Sexual violence in the workplace and associated health outcomes: a nationwide, cross-sectional analysis of women in Iceland.

BACKGROUND: Workplace sexual violence against women is a pressing global issue with scarce knowledge on its health implications. Existing research is largely limited to specific occupations, which calls for comprehensive, population-based studies. This study aimed to examine the associations between self-labelled workplace sexual violence and a variety of health outcomes in a nationally representative sample of Icelandic women aged 18-69 years. METHODS: Participants in this cross-sectional study were women in the Stress-And-Gene-Analysis (SAGA) cohort who answered the question regarding workplace sexual violence, defined in our study as encompassing all work sectors, academic settings, and other school environments. Eligible participants were women, aged 18-69 years, residing in Iceland, who spoke Icelandic and were listed in the Icelandic Population Register or had a contact number registered with the online 1819 service. Poisson and binomial regressions were used to assess the associations between workplace sexual violence and validated measures of current mental and physical health outcomes (eg, probable depression, general anxiety, and severe sleep problems). Multiple imputation was performed to account for missing values in the dataset. FINDINGS: The study was conducted from March 1, 2018, to July 1, 2019. Of the 113 814 women deemed eligible for study inclusion, 104 197 were invited to take part in the online survey. Of those invited, 30 403 women completed the survey and were included in the SAGA cohort. Among these participants, 15 812 provided answers to the question regarding exposure to workplace sexual harassment or violence. Exposure to sexual violence was associated with an increased prevalence of probable depression (prevalence ratio [PR] 1·50 [95% CI 1·41-1·60]), general anxiety (PR 1·49 [1·40-1·59]), social phobia (PR 1·62 [1·48-1·78]), self-harm (PR 1·86 [1·53-2·28]), suicidal ideation (PR 1·68 [1·44-1·68]), suicide attempts (PR 1·99 [1·62-2·44]), binge drinking (PR 1·10 [1·01-1·20]), sleep problems (PR 1·41 [1·48-1·91]), physical symptoms (PR 1·59 [1·48-1·70]), and sick leave (PR 1·20 [1·12-1·28]). The prevalence of the health outcomes among those exposed show age-related differences: younger women report anxiety or depression more frequently, while older women report sleep problems after experiencing workplace sexual violence. INTERPRETATION: In this cross-sectional study self-reported experiences of sexual violence in the workplace were associated with several self-reported health outcomes. The findings suggest a need for targeted interventions to promote workplace safety and to mitigate adverse health implications among people who have experienced workplace sexual violence. Future research should explore factors such as the frequency, duration, and relationship dynamics of workplace sexual violence, as well as the effect on different genders and sexual orientations, to deepen our understanding of these experiences and inform effective prevention strategies. FUNDING: Reykjavík Energy Research Fund, The Icelandic Gender Equality Fund, European Research Council, and Icelandic Center for Research.

Adverse Childhood Experiences and Adult Mental Health Outcomes.

Importance: Exposure to adverse childhood experiences (ACEs) has consistently been associated with multiple negative mental health outcomes extending into adulthood. However, given that ACEs and psychiatric disorders cluster within families, it remains to be comprehensively assessed to what extent familial confounding contributes to associations between ACEs and clinically confirmed adult psychiatric disorders. Objective: To investigate whether associations between ACEs and adult mental health outcomes remain after adjusting for familial (genetic and environmental) confounding. Design, Setting, and Participants: This Swedish twin cohort study used a discordant twin pair design based on monozygotic (MZ) and dizygotic (DZ) twins. A total of 25 252 adult twins (aged 18-47 years) from the Swedish Twin Registry born between 1959 and 1998 were followed up from age 19 years until 2016, with a maximum follow-up time of 39 years. Data were analyzed from April 2022 to November 2023. Exposures: A total of 7 ACEs, including family violence, emotional abuse or neglect, physical neglect, physical abuse, sexual abuse, rape, and hate crime, were assessed with items from the Life Stressor Checklist-Revised in a web-based survey. Main Outcomes and Measures: Adult (ages >18 years) clinical diagnosis of psychiatric disorders (ie, depressive, anxiety, alcohol or drug misuse, or stress-related disorders) were obtained from the Swedish National Patient Register. Results: Of 25 252 twins included in the study (15 038 female [59.6%]; mean [SD] age at ACE assessment, 29.9 [8.7] years), 9751 individuals (38.6%) reported exposure to at least 1 ACE. A greater number of ACEs was associated with increased odds of any psychiatric disorder in the full cohort (odds ratio [OR] per additional ACE, 1.52; 95% CI, 1.48-1.57). The association remained but ORs per additional ACE were attenuated in DZ (1.29; 95% CI, 1.14-1.47) and MZ (1.20; 95% CI, 1.02-1.40) twin pairs. Individuals who were exposed to sexual abuse compared with those who were not exposed had increased odds of any clinically confirmed psychiatric disorder in all comparisons: full cohort (OR, 3.09; 95% CI, 2.68-3.56), DZ twin pairs (OR, 2.10; 95% CI, 1.33-3.32), and MZ twin pairs (1.80; 95% CI, 1.04-3.11). Conclusions and relevance: This study found that associations between ACEs and adult mental health outcomes remained after controlling for shared genetic and environmental factors, which was particularly evident after multiple ACEs or sexual abuse. These findings suggest that targeted interventions may be associated with reduced risks of future psychopathology.

Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Elevated symptoms of depression and anxiety among family members and friends of critically ill COVID-19 patients - an observational study of five cohorts across four countries.

Background: Little is known regarding the mental health impact of having a significant person (family member and/or close friend) with COVID-19 of different severity. Methods: The study included five prospective cohorts from four countries (Iceland, Norway, Sweden, and the UK) with self-reported data on COVID-19 and symptoms of depression and anxiety during March 2020-March 2022. We calculated prevalence ratios (PR) of depression and anxiety in relation to having a significant person with COVID-19 and performed a longitudinal analysis in the Swedish cohort to describe temporal patterns. Findings: 162,237 and 168,783 individuals were included in the analysis of depression and anxiety, respectively, of whom 24,718 and 27,003 reported a significant person with COVID-19. Overall, the PR was 1.07 (95% CI: 1.05-1.10) for depression and 1.08 (95% CI: 1.03-1.13) for anxiety in relation to having a significant person with COVID-19. The respective PRs for depression and anxiety were 1.15 (95% CI: 1.08-1.23) and 1.24 (95% CI: 1.14-1.34) if the patient was hospitalized, 1.42 (95% CI: 1.27-1.57) and 1.45 (95% CI: 1.31-1.60) if the patient was ICU-admitted, and 1.34 (95% CI: 1.22-1.46) and 1.36 (95% CI: 1.22-1.51) if the patient died. Individuals with a significant person with hospitalized, ICU-admitted, or fatal COVID-19 showed elevated prevalence of depression and anxiety during the entire year after the COVID-19 diagnosis. Interpretation: Family members and close friends of critically ill COVID-19 patients show persistently elevated prevalence of depressive and anxiety symptoms. Funding: This study was primarily supported by NordForsk (COVIDMENT, 105668) and Horizon 2020 (CoMorMent, 847776).

COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark.

Background: Although the persistence of physical symptoms after SARS-CoV-2 infection is a major public health concern, evidence from large observational studies beyond one year post diagnosis remain scarce. We aimed to assess the prevalence of physical symptoms in relation to acute illness severity up to more than 2-years after diagnosis of COVID-19. Methods: This multinational study included 64,880 adult participants from Iceland, Sweden, Denmark, and Norway with self-reported data on COVID-19 and physical symptoms from April 2020 to August 2022. We compared the prevalence of 15 physical symptoms, measured by the Patient Health Questionnaire (PHQ-15), among individuals with or without a confirmed COVID-19 diagnosis, by acute illness severity, and by time since diagnosis. We additionally assessed the change in symptoms in a subset of Swedish adults with repeated measures, before and after COVID-19 diagnosis. Findings: During up to 27 months of follow-up, 34.5% participants (22,382/64,880) were diagnosed with COVID-19. Individuals who were diagnosed with COVID-19, compared to those not diagnosed, had an overall 37% higher prevalence of severe physical symptom burden (PHQ-15 score ≥15, adjusted prevalence ratio [PR] 1.37 [95% confidence interval [CI] 1.23-1.52]). The prevalence was associated with acute COVID-19 severity: individuals bedridden for seven days or longer presented with the highest prevalence (PR 2.25 [1.85-2.74]), while individuals never bedridden presented with similar prevalence as individuals not diagnosed with COVID-19 (PR 0.92 [0.68-1.24]). The prevalence was statistically significantly elevated among individuals diagnosed with COVID-19 for eight of the fifteen measured symptoms: shortness of breath, chest pain, dizziness, heart racing, headaches, low energy/fatigue, trouble sleeping, and back pain. The analysis of repeated measurements rendered similar results as the main analysis. Interpretation: These data suggest an elevated prevalence of some, but not all, physical symptoms during up to more than 2 years after diagnosis of COVID-19, particularly among individuals suffering a severe acute illness, highlighting the importance of continued monitoring and alleviation of these targeted core symptoms. Funding: This work was mainly supported by grants from NordForsk (COVIDMENT, grant number 105668 and 138929) and Horizon 2020 (CoMorMent, 847776). See Acknowledgements for further details on funding.

Interpretation of genetic association studies: markers with replicated highly significant odds ratios may be poor classifiers.

Recent successful discoveries of potentially causal single nucleotide polymorphisms (SNPs) for complex diseases hold great promise, and commercialization of genomics in personalized medicine has already begun. The hope is that genetic testing will benefit patients and their families, and encourage positive lifestyle changes and guide clinical decisions. However, for many complex diseases, it is arguable whether the era of genomics in personalized medicine is here yet. We focus on the clinical validity of genetic testing with an emphasis on two popular statistical methods for evaluating markers. The two methods, logistic regression and receiver operating characteristic (ROC) curve analysis, are applied to our age-related macular degeneration dataset. By using an additive model of the CFH, LOC387715, and C2 variants, the odds ratios are 2.9, 3.4, and 0.4, with p-values of 10(-13), 10(-13), and 10(-3), respectively. The area under the ROC curve (AUC) is 0.79, but assuming prevalences of 15%, 5.5%, and 1.5% (which are realistic for age groups 80 y, 65 y, and 40 y and older, respectively), only 30%, 12%, and 3% of the group classified as high risk are cases. Additionally, we present examples for four other diseases for which strongly associated variants have been discovered. In type 2 diabetes, our classification model of 12 SNPs has an AUC of only 0.64, and two SNPs achieve an AUC of only 0.56 for prostate cancer. Nine SNPs were not sufficient to improve the discrimination power over that of nongenetic predictors for risk of cardiovascular events. Finally, in Crohn's disease, a model of five SNPs, one with a quite low odds ratio of 0.26, has an AUC of only 0.66. Our analyses and examples show that strong association, although very valuable for establishing etiological hypotheses, does not guarantee effective discrimination between cases and controls. The scientific community should be cautious to avoid overstating the value of association findings in terms of personalized medicine before their time.

Association between Adverse Childhood Experiences and Multiple Sclerosis in Icelandic Women-A Population-Based Cohort Study.

BACKGROUND: A growing literature, mostly based on selected populations, indicates that traumas may be associated with autoimmune diseases, yet few studies exist on adverse childhood experiences (ACEs) and multiple sclerosis (MS) in the general population. OBJECTIVE: We assessed cross-sectional associations between self-reported ACEs and MS among Icelandic women in the population-based Stress-And-Gene-Analysis (SAGA) cohort. METHODS: Participants (n = 27,870; mean age 44.9 years) answered a web-based survey that included the ACE-International Questionnaire and a question about MS diagnosis. Log-linear Poisson regression models estimated MS prevalence ratios and 95% confidence intervals for ACEs adjusted for covariates. RESULTS: 214 women reported having been diagnosed with MS (crude prevalence = 7.7 per 1000). Compared to women without MS, women with MS reported more fatigue, body pain and bladder problems. The average cumulative number of ACEs was 2.1. After adjustment for age, education, childhood deprivation, smoking and depressive symptoms, MS prevalence did not increase with increasing ACEs exposure (PR = 1.00, 95% CI = 0.92, 1.09). Thirteen ACE categories, including abuse, neglect, household dysfunction and violence were not individually or independently associated with MS. CONCLUSION: Limited by self-reported data and cross-sectional design, results do not consistently support associations between ACEs in the development of MS among adult Icelandic women.