Is an Early Age at Illness Onset in Schizophrenia Associated With Increased Genetic Susceptibility?

Background: Early age at illness onset has been viewed as an important liability marker for schizophrenia, which may be associated with an increased genetic vulnerability. A twin approach can be valuable, because it allows for the investigation of specific illness markers in individuals with a shared genetic background. Methods: We linked nationwide registers to identify a cohort of twin pairs born in Denmark from 1951 to 2000 (N = 31,524 pairs), where one or both twins had a diagnosis in the schizophrenia spectrum. We defined two groups consisting of; N = 788 twin pairs (affected with schizophrenia spectrum) and a subsample of N = 448 (affected with schizophrenia). Survival analysis was applied to investigate the effect of age at illness onset. Findings: We found that early age at illness onset compared to later onset in the first diagnosed twin can be considered a major risk factor for developing schizophrenia in the second twin. Additionally, we found that the stronger genetic component in MZ twins compared to DZ twins is manifested in the proximity of assigned diagnosis within pairs. Discussion: Early onset schizophrenia could be linked to a more severe genetic predisposition, indicating that age might be perceived as a clinical marker for genetic vulnerability for the illness

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

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P= 3.96 x 10(-14)). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.Peer reviewe

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P= 3.96 x 10(-14)). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality

Correction : The association between medication for attention-deficit/hyperactivity disorder and cancer

Objective: A study on chromosomal abnormalities has raised concerns that medication with methylphenidate (MPH) for attention-deficit/hyperactivity disorders (ADHD) might increase the risk of cancer. We performed a rigorous test of the association between cancer and MPH and other drugs used for ADHD, based on data from nationwide Danish registers. Methods: Data were linked from five registers containing information on a total of 21,186 patients with ADHD, their drug prescription rates, and associated cancer diagnoses between 1994 and 2010. The cohort included subgroups treated with MPH only, amphetamines only, other ADHD-specific drugs only, antidepressants only, antipsychotics only, mixed medication, and a control group of patients with ADHD who had never taken medication. Frequencies of cancer diagnoses in these groups were compared. In addition, hazard risk (HR) ratios for developing cancer, and survival rates in these subgroups, were analyzed. Results: The mean observation time varied between 1.3 and 10.8 years for the various drugs. Cancer rates in the total group amounted to 1.27 per 10 000 person-years before and to 4.33 per 10 000 person-years after onset of treatment. The frequency of cancer was significantly higher (p=0.05) after than before medication only in the antipsychotics subgroup. Furthermore, for mixed medication, the cancer frequency in a small subgroup was significantly higher (p<0.05) after onset of medication than in the unmedicated subgroup. The Cox regression analysis indicated that none of the drugs represented risk factors, whereas higher dose (p<0.001) and older age (p<0.05) were risk factors for developing cancer. Conclusions: The concern that children taking MPH and other drugs over long periods of time could be at a significant risk of developing cancer is not substantiated by these findings in a large and representative sample, which had been diagnosed and treated over a period of 17 years

A three generations nation-wide population study of family load estimates in bipolar disorder with different age at onset

OBJECTIVES: This nation-wide register-based study investigates how often bipolar disorder (BD) occurs in affected families compared to control families by estimating the family load as a random effect; this effect measures the degree of dependence among family members in relation to BD. Furthermore, the study addresses the impact of certain risk factors, namely, sex, age at onset of BD, degree of urbanization, year of birth, month of birth, and maternal and paternal age at birth. METHOD: A total of N=1204 children and adolescent psychiatric cases born between 1950 and 1997 and registered in the Danish Central Psychiatric Register (DPCR) developed BD before the age of 58 years. N=3553 controls without any psychiatric diagnosis were matched for age, gender, and region of residence. Psychiatric diagnoses were also obtained on the relatives, e.g. parents, siblings, and offspring as a part of the Danish Three Generation Study (3GS). A family component was obtained by using different regression models. RESULTS: Familial factors accounted for 20% of the variation in disease outcome when controlling for year and month of birth, sex, and degree of urbanization. Only female sex was associated with an increased hazard ratio of BD. Also having a mother, father or a sibling with the disorder was proven to be a significant risk factor. Furthermore, case relatives did not develop BD earlier than control relatives. CONCLUSION: These findings based on a very large and representative dataset provide further and very solid evidence for the high family aggregation of BD