In Pursuit of Clarity:Understanding the biology of schizophrenia by functional investigations and integrative genomic data analyses

Schizophrenia is a complex and heterogenous illness for which the underlying biology is largely unknown. Using functional investigations and integrative genomic data analyses, this thesis sheds light on the biological causes and consequences of schizophrenia

Longitudinal analyses of depression, anxiety, and suicidal ideation highlight greater prevalence in the northern Dutch population during the COVID-19 lockdowns

BACKGROUND: The pandemic of the coronavirus disease 2019 (COVID-19) has led to an increased burden on mental health. AIMS: To investigate the development of major depressive disorder (MDD), generalized anxiety disorder (GAD), and suicidal ideation in the Netherlands during the first fifteen months of the pandemic and three nation-wide lockdowns. METHOD: Participants of the Lifelines Cohort Study –a Dutch population-based sample-reported current symptoms of MDD and GAD, including suicidal ideation, according to DSM-IV criteria. Between March 2020 and June 2021, 36,106 participants (aged 18–96) filled out a total of 629,811 questionnaires across 23 time points. Trajectories over time were estimated using generalized additive models and analyzed in relation to age, sex, and lifetime history of MDD/GAD. RESULTS: We found non-linear trajectories for MDD and GAD with a higher number of symptoms and prevalence rates during periods of lockdown. The point prevalence of MDD and GAD peaked during the third hard lockdown at 2.88 % (95 % CI: 2.71 %–3.06 %) and 2.92 % (95 % CI: 2.76 %–3.08 %), respectively, in March 2021. Women, younger adults, and participants with a history of MDD/GAD reported significantly more symptoms. For suicidal ideation, we found a significant linear increase over time in younger participants. For example, 20-year-old participants reported 4.14× more suicidal ideation at the end of June 2021 compared to the start of the pandemic (4.64 % (CI: 3.09 %–6.96 %) versus 1.12 % (CI: 0.76 %–1.66 %)). LIMITATIONS: Our findings should be interpreted in relation to the societal context of the Netherlands and the public health response of the Dutch government during the pandemic, which may be different in other regions in the world. CONCLUSIONS: Our study showed greater prevalence of MDD and GAD during COVID-19 lockdowns and a continuing increase in suicidal thoughts among young adults suggesting that the pandemic and government enacted restrictions impacted mental health in the population. Our findings provide actionable insights on mental health in the population during the pandemic, which can guide policy makers and clinical care during future lockdowns and epi/pandemics

Methylation age acceleration does not predict mortality in schizophrenia.

Schizophrenia (SCZ) is associated with high mortality. DNA methylation levels vary over the life course, and pre-selected combinations of methylation array probes can be used to estimate "methylation age" (mAge). mAge correlates highly with chronological age but when it differs, termed mAge acceleration, it has been previously associated with all-cause mortality. We tested the association between mAge acceleration and mortality in SCZ and controls. We selected 190 SCZ cases and 190 controls from the Sweden Schizophrenia Study. Cases were identified from the Swedish Hospital Discharge Register with ≥5 specialist treatment contacts and ≥5 antipsychotic prescriptions. Controls had no psychotic disorder or antipsychotics. Subjects were selected if they had died or survived during follow-up (2:1 oversampling). Extracted DNA was assayed on the Illumina MethylationEPIC array. mAge was regressed on age at sampling to obtain mAge acceleration. Using Cox proportional hazards regression, the association between mAge acceleration and mortality was tested. After quality control, the following were available: n = 126 SCZ died, 63 SCZ alive, 127 controls died, 62 controls alive. In the primary analyses, we did not find a significant association between mAge acceleration and SCZ mortality (adjusted p > 0.005). Sensitivity analyses excluding SCZ cases with pre-existing cancer demonstrated a significant association between the Hannum mAge acceleration and mortality (hazard ratio = 1.13, 95% confidence interval = 1.04-1.22, p = 0.005). Per our pre-specified criteria, we did not confirm our primary hypothesis that mAge acceleration would predict subsequent mortality in people with SCZ, but we cannot rule out smaller effects or effects in patient subsets

The association of sex, age and FKBP5 genotype with common somatic symptoms:A replication study in the lifelines cohort study

OBJECTIVE: Our aim was to replicate a recent study that reported an association between the rs9470080 CC-genotype and common somatic symptoms in women, but not in men. Additionally, we quantified the genetic contribution to phenotypic variation in common somatic symptom levels. METHODS: We used data from the Lifelines Cohort Study, including 28,299 participants (60.0% female; 44.2% CC-genotype; mean age 42.9 (14.2) years). Common somatic symptoms were measured with the SCL-90 SOM subscale. To assess the association between the rs9470080 genotype and SCL-90 SOM scores we applied similar analyses as the original study, including independent t-tests, two-way ANOVAs and a mixed ANOVA. To estimate the proportion of phenotypic variance in SCL-90 SOM scores explained by single nucleotide polymorphisms (SNPs), we used a genomic-relatedness-based restricted maximum-likelihood method. RESULTS: We could not replicate the original study's findings. We found no association between the rs9470080 genotype and common somatic symptom levels in either female or male participants (F(1, 8775) = 1.07, p = 0.30 and F(1,13,903) = 0.01, p = 0.93, respectively). Genome-wide heritability analyses show that 12.1% (p = 2.1e-08) of the phenotypic variance in common somatic symptom levels in Lifelines can be explained by SNPs. The genetic contribution to common somatic symptom levels was higher in male participants (SNP-h2 = 20.5%; p = 9.1e-08) than in female participants (SNP-h2 = 12.0%, p = 2.8e-05). CONCLUSION: Our findings of significant SNP-h2 and the sex-specific differences herein, does warrant further sex-stratified research of individual genetic variants associated with common somatic symptoms. Preferably, further research should be performed within the analytic framework of a genome-wide association study

Loneliness associates strongly with anxiety and depression during the COVID pandemic, especially in men and younger adults

Loneliness is associated with major depressive disorder (MDD), and likely also with generalized anxiety disorder (GAD). It is unclear if these associations are moderated by age, sex, or genetic susceptibility for MDD. We included 75,279 individuals from the Lifelines COVID-19 study, a longitudinal study of a Dutch population-based cohort. Participants completed up to sixteen digital questionnaires between March 2020 and January 2021, yielding a total of 616,129 observations. Loneliness was assessed with the Three-Item Loneliness Scale, and MDD and GAD with the Mini-International Neuropsychiatric Interview. We used generalized estimating equations to investigate the association between loneliness and MDD and GAD, and whether this association varied across time, age, sex and MDD polygenic risk. Loneliness was strongly associated with all MDD and GAD outcomes. Individuals with the highest loneliness scores were around 14 times more likely to have MDD, and 11 times more likely to have GAD, compared to individuals who reported the least loneliness. The association between loneliness and MDD symptoms was stronger in men, younger individuals, and increased across time. While MDD polygenic risk predicted MDD and GAD outcomes, we did not find an interaction effect with loneliness. Our study, which is the largest to date, confirms that loneliness is an important risk factor for MDD, GAD, depressive and anxiety symptoms, especially in men and younger individuals. Future studies should investigate the mechanisms of these associations and explore loneliness-based interventions to prevent and treat MDD and GAD

Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility

Epidemiological and genetic studies on COVID-19 are currently hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict COVID-19 cases using cross-sectional self-reported disease-related symptoms. Here, we demonstrate that this COVID-19 prediction model has reasonable and consistent performance across multiple independent cohorts and that our attempt to improve upon this model did not result in improved predictions. Using the existing COVID-19 prediction model, we then conducted a GWAS on the predicted phenotype using a total of 1,865 predicted cases and 29,174 controls. While we did not find any common, large-effect variants that reached genome-wide significance, we do observe suggestive genetic associations at two SNPs (rs11844522, p = 1.9x10-7; rs5798227, p = 2.2x10-7). Explorative analyses furthermore suggest that genetic variants associated with other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. This study represents a first effort that uses a symptom-based predicted phenotype as a proxy for COVID-19 in our pursuit of understanding the genetic susceptibility of the disease. We conclude that the inclusion of symptom-based predicted cases could be a useful strategy in a scenario of limited testing, either during the current COVID-19 pandemic or any future viral outbreak.Peer reviewe

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants