Genetics of age-related maculopathy & Score statistics for X-linked quantitative trait loci

Age-related maculopathy (ARM) is a common cause of irreparable vision loss in industrialized countries. The disease is characterized by progressive loss of central vision making everyday tasks challenging. The etiology is complex and has both an environmental and a strong genetic components. The public health relevance of the work is to improve the understanding genetic causes in the disease etiology and ultimately to lead to better disease management and prevention. From my ARM work, I present four papers covering range of statistical approaches. The first paper presents fine-mapping efforts, using both linkage and association methods, under previously identified linkage peaks on chromosomes 1q31 and 10q26. We replicate the discovery of the complement factor H (CFH) gene on 1q31 and identify a novel locus, harboring three closely linked genes (PLEKHA1, LOC387715, and HTRA1), on 10q26. Both discoveries have been widely replicated. In the next paper I present meta-analysis of 11 CFH and 5 LOC387715 data sets. We also replicate these findings in two independent case-control cohorts, including one cohort, where ARM status was not a factor in the ascertainment. In the third paper we replicate discoveries of new complement related loci (C2 and CFB) on chromosome 19p13 as well as developing classification models based on SNPs from CFH, LOC387715, and C2. The last paper focuses on applying statistical techniques from the diagnostic medicine literature to ARM. We comment on the importance of understanding the difference and similarities between different goals of genetic studies: improving etiological understanding or finding variants that discriminate well between cases and controls. This work is particularly relevant today when there has been explosion in the availability of direct-to-consumer DNA tests.In addition to carrying out linkage and association analysis, I also have extended the statistical theory behind score-based linkage analyses for X chromosomal markers. This work has public health relevance because many complex common diseases have sex-specific differences, such as prevalence and age of onset. Modeling those appropriately with powerful and robust methods will bring an improved understanding of their genetic basis

Sleep disturbances among women in a Subarctic region: a nationwide study

Funding Information: Approval for the study was granted by the Icelandic Bioethics Committee (nr. VSNb2017110046/03.01) Publisher Copyright: © 2022 Sleep Research Society. Published by Oxford University Press on behalf of the Sleep Research Society.STUDY OBJECTIVES: To date, few studies have assessed sleep problems among women residing in Subarctic regions. Therefore, the aim of this large-scale population-based study was to assess the prevalence of severe sleep problems and associated factors among Icelandic women, living at 63-66°N. METHODS: Participants were 29 681 women (18-69 years old) who took part in the Icelandic Stress-And-Gene-Analysis study in 2018-2019. Background information, health-related behavior, and mental health symptoms were assessed with an online questionnaire. The Pittsburgh Sleep Quality Index (PSQI) was used to assess severe sleep problems during the past month. Adjusting for age, marital status, number of children, education, personal income, work schedule, region, and response period, we used modified Poisson log-linear models to obtain prevalence ratios (PRs) with 95% confidence intervals (CIs). RESULTS: Overall, 24.2% of women reported severe sleep problems (PSQI >10). Women responding in the winter presented with an overall higher prevalence of severe sleep problems, compared to those responding in the summer (PR 1.21; 95% CI, 1.15 to 1.28). Severe sleep problems were more prevalent among young and late-midlife women, those who were single, had children, socio-economic challenges, worked shifts, and flexible hours. Furthermore, obesity, suboptimal health behaviors, excessive screen time, and mental health problems were associated with severe sleep problems. CONCLUSION: Severe sleep problems are more common among women in Subarctic regions than elsewhere, particularly during winter. These findings motivate the development of preventive strategies and interventions for women in the Subarctic who suffer from sleep problems.Peer reviewe

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.Peer reviewe

Cardiovascular disease and subsequent risk of psychiatric disorders: a nationwide sibling-controlled study

Background: The association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while the potential role of familial factors and comorbidities in such association has rarely been investigated. Methods: We identified 869 056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden with no history of psychiatric disorders, and 910 178 full siblings of these patients as well as 10 individually age- and sex-matched unrelated population controls (N=8 690 560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox models to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls. Results: The median age at diagnosis was 60 years for patients with CVD and 59.2% were male. During up to thirty years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6 and 4.0 per 1000 person-years for patients with CVD, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after CVD diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62-2.87) and thereafter (1.45; 95% CI, 1.42-1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of CVD. We observed similar associations in the population comparison. CVD patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at elevated risk of subsequent CVD death compared to patients without such comorbidity (HR 1.55; 95% CI 1.44-1.67). Conclusions: Patients diagnosed with CVD are at an elevated risk for subsequent psychiatric disorders independent of shared familial factors and comorbid conditions. Comorbid psychiatric disorders in patients with CVD are associated with higher risk of cardiovascular mortality suggesting that surveillance and treatment of psychiatric comorbidities should be considered as an integral part of clinical management of newly diagnosed CVD patients. Funding: This work was supported by the EU Horizon 2020 Research and Innovation Action Grant (CoMorMent, grant no. 847776 to UV, PFS and FF), Grant of Excellence, Icelandic Research Fund (grant no. 163362-051 to UV), ERC Consolidator Grant (StressGene, grant no: 726413 to UV), Swedish Research Council (grant no. D0886501 to PFS) and US NIMH R01 MH123724 (to PFS)

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 (β = 2.79, 95% CI = 1.19-4.38) and anxiety (β = 2.04, 95% CI = 0.99-3.09) including poorer sleep quality (β = 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.Peer reviewe

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

Funding Information: Open access funding provided by Karolinska Institute. The work is supported by the Erik and Edith Fernström Foundation (No. 2019-00415 to Dr. Yang), the Chinese Scholarship Council (No. 201700260289 to Dr. Yang), the Icelandic Research Fund (No. 185287-051 to Dr. Þórðardóttir), the Swedish Research Council for Health, Working Life and Welfare (FORTE) (No. 2020-00971 to Dr. Lu), the Swedish Research Council (Vetenskapsrådet) (No. 2020-01003 to Dr. Lu), and the Grant of Excellence from the Icelandic Research Fund (No. 163362-051 and 218274-051 to Dr. Valdimarsdóttir) and European Research Council (No. 726413 to Dr. Valdimarsdóttir). Researchers are independent of the funders. The funding has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Publisher Copyright: © 2022, The Author(s).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.Peer reviewe

Mental illness and COVID-19 vaccination: a multinational investigation of observational & register-based data

Individuals with mental illness are at higher risk of severe COVID-19 outcomes. However, previous studies on the uptake of COVID-19 vaccination in this population have reported conflicting results. Using data from seven cohort studies (N = 325,298) included in the multinational COVIDMENT consortium, and the Swedish registers (N = 8,080,234), this study investigates the association between mental illness (defined using self-report measures, clinical diagnosis and prescription data) and COVID-19 vaccination uptake. Results from the COVIDMENT cohort studies were pooled using meta-analyses, the majority of which showed no significant association between mental illness and vaccination uptake. In the Swedish register study population, we observed a very small reduction in the uptake of both the first and second dose of a COVID-19 vaccine among individuals with vs. without mental illness; the reduction was however greater among those not using psychiatric medication. Here we show that uptake of the COVID-19 vaccine is generally high among individuals both with and without mental illness, however the lower levels of vaccination uptake observed among subgroups of individuals with unmedicated mental illness warrants further attention

Acute COVID-19 severity and mental health morbidity trajectories in patient populations of six nations: an observational study

Background Long-term mental and physical health consequences of COVID-19 (long COVID) are a persistent public health concern. Little is still known about the long-term mental health of non-hospitalised patients with COVID-19 with varying illness severities. Our aim was to assess the prevalence of adverse mental health symptoms among individuals diagnosed with COVID-19 in the general population by acute infection severity up to 16 months after diagnosis. Methods This observational follow-up study included seven prospectively planned cohorts across six countries (Denmark, Estonia, Iceland, Norway, Sweden, and the UK). Participants were recruited from March 27, 2020, to Aug 13, 2021. Individuals aged 18 years or older were eligible to participate. In a cross-sectional analysis, we contrasted symptom prevalence of depression, anxiety, COVID-19-related distress, and poor sleep quality (screened with validated mental health instruments) among individuals with and without a diagnosis of COVID-19 at entry, 0–16 months from diagnosis. In a cohort analysis, we further used repeated measures to estimate the change in mental health symptoms before and after COVID-19 diagnosis. Findings The analytical cohort consisted of 247 249 individuals, 9979 (4·0%) of whom were diagnosed with COVID-19 during the study period. Mean follow-up was 5·65 months (SD 4·26). Participants diagnosed with COVID-19 presented overall with a higher prevalence of symptoms of depression (prevalence ratio [PR] 1·18 [95% CI 1·03–1·36]) and poorer sleep quality (1·13 [1·03–1·24]) but not symptoms of anxiety (0·97 [0·91–1·03]) or COVID-19-related distress (1·05 [0·93–1·20]) compared with individuals without a COVID-19 diagnosis. Although the prevalence of depression and COVID-19-related distress attenuated with time, individuals diagnosed with COVID-19 but never bedridden due to their illness were consistently at lower risk of depression (PR 0·83 [95% CI 0·75–0·91]) and anxiety (0·77 [0·63–0·94]) than those not diagnosed with COVID-19, whereas patients who were bedridden for more than 7 days were persistently at higher risk of symptoms of depression (PR 1·61 [95% CI 1·27–2·05]) and anxiety (1·43 [1·26–1·63]) than those not diagnosed throughout the study period. Interpretation Severe acute COVID-19 illness—indicated by extended time bedridden—is associated with long-term mental morbidity among recovering individuals in the general population. These findings call for increased vigilance of adverse mental health development among patients with a severe acute disease phase of COVID-19.Funding Nordforsk, Horizon2020, Wellcome Trust, and Estonian Research Council

Adverse childhood experiences and resilience among adult women : A population-based study

© 2022, Daníelsdóttir et al. Funding Information: Funding: This work was supported by the European Research Council (Consolidator grant; UAV, grant number 726413), and the Icelandic Center for Research (Grant of excellence; UAV, grant number 163362-051). HBD was supported by a doctoral grant from the University of Iceland Research Fund. Funding Information: This work was supported by the European Research Council (UAV, grant number 726413), and the Icelandic Center for Research (Grant of excellence; UAV, grant number 163362?051). HBD was supported by a doctoral grant from the University of Iceland Research Fund. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.Funder Grant reference number Author Icelandic Centre for Research H2020 European Research Council Icelandic Centre for Research Doctoral grant Consolidator grant grant number 726413 Grant of excellence grant number 163362-051 Hilda Bj?rk Dan?elsd?ttir Unnur Anna Valdimarsd?ttir Unnur Anna Valdimarsd?ttir The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding Information: Funding This work was supported by the European Research Council (UAV, grant number 726413), and the Icelandic Center for Research (Grant of excellence; UAV, grant number 163362–051). HBD was supported by a doctoral grant from the University of Iceland Research Fund. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: © Daníelsdóttir et al.Background: Adverse childhood experiences (ACEs) have consistently been associated with elevated risk of multiple adverse health outcomes, yet their contribution to coping ability and psychiatric resilience in adulthood is unclear. Methods: Cross-sectional data were derived from the ongoing Stress-And-Gene-Analysis cohort, representing 30% of the Icelandic nationwide female population, 18-69 years. Participants in the current study were 26,198 women with data on 13 ACEs measured with the ACE-International Questionnaire. Self-reported coping ability was measured with the Connor-Davidson Resilience Scale and psychiatric resilience was operationalized as absence of psychiatric morbidity. Generalized linear regression assuming normal or Poisson distribution were used to assess the associations of ACEs with coping ability and psychiatric resilience controlling for multiple confounders. Results: Number of ACEs was inversely associated with adult resilience in a dose-dependent manner; every 1SD unit increase in ACE scores was associated with both lower levels of coping ability ( β = -0.14; 95% CI-0.15,-0.13) and lower psychiatric resilience ( β = -0.28; 95% CI-0.29,-0.27) in adulthood. Compared to women with 0 ACEs, women with ≥5 ACEs had 36% lower prevalence of high coping ability (PR = 0.64, 95% CI 0.59,0.70) and 58% lower prevalence of high psychiatric resilience (PR = 0.42; 95% CI 0.39,0.45). Specific ACEs including emotional neglect, bullying, sexual abuse and mental illness of household member were consistently associated with reduced adult resilience. We observed only slightly attenuated associations after controlling for adult socioeconomic factors and social support in adulthood. Conclusions: Cumulative ACE exposure is associated with lower adult resilience among women, independent of adult socioeconomic factors and social support, indicating that adult resilience may be largely determined in childhood. Funding: This work was supported by the European Research Council (Consolidator grant; UAV, grant number 726413), and the Icelandic Center for Research (Grant of excellence; UAV, grant number 163362-051). HBD was supported by a doctoral grant from the University of Iceland Research Fund.Peer reviewe