Milk and bugs educate infant immune systems.

Immune-system maturation starts early in life, but studies investigating immune-system education in human infants remain scarce. In a recent issue of Cell, Henrick et al. study early gut microbiota and immune-system development in two infant cohorts. The authors describe that Bifidobacteria can use milk sugars to produce immunoregulatory compounds that induce immune tolerance and reduce intestinal inflammation.

Dearomatization drives complexity generation in freshwater organic matter.

Dissolved organic matter (DOM) is one of the most complex, dynamic and abundant sources of organic carbon, but its chemical reactivity remains uncertain1-3. Greater insights into DOM structural features could facilitate understanding its synthesis, turnover and processing in the global carbon cycle4,5. Here we use complementary multiplicity-edited 13C nuclear magnetic resonance (NMR) spectra to quantify key substructures assembling the carbon skeletons of DOM from four main Amazon rivers and two mid-size Swedish boreal lakes. We find that one type of reaction mechanism, oxidative dearomatization (ODA), widely used in organic synthetic chemistry to create natural product scaffolds6-10, is probably a key driver for generating structural diversity during processing of DOM that are rich in suitable polyphenolic precursor molecules. Our data suggest a high abundance of tetrahedral quaternary carbons bound to one oxygen and three carbon atoms (OCqC3 units). These units are rare in common biomolecules but could be readily produced by ODA of lignin-derived and tannin-derived polyphenols. Tautomerization of (poly)phenols by ODA creates non-planar cyclohexadienones, which are subject to immediate and parallel cycloadditions. This combination leads to a proliferation of structural diversity of DOM compounds from early stages of DOM processing, with an increase in oxygenated aliphatic structures. Overall, we propose that ODA is a key reaction mechanism for complexity acceleration in the processing of DOM molecules, creation of new oxygenated aliphatic molecules and that it could be prevalent in nature.

Financial incentives for vaccination do not have negative unintended consequences.

Financial incentives to encourage healthy and prosocial behaviours often trigger initial behavioural change1-11, but a large academic literature warns against using them12-16. Critics warn that financial incentives can crowd out prosocial motivations and reduce perceived safety and trust, thereby reducing healthy behaviours when no payments are offered and eroding morals more generally17-24. Here we report findings from a large-scale, pre-registered study in Sweden that causally measures the unintended consequences of offering financial incentives for taking the first dose of a COVID-19 vaccine. We use a unique combination of random exposure to financial incentives, population-wide administrative vaccination records and rich survey data. We find no negative consequences of financial incentives; we can reject even small negative impacts of offering financial incentives on future vaccination uptake, morals, trust and perceived safety. In a complementary study, we find that informing US residents about the existence of state incentive programmes also has no negative consequences. Our findings inform not only the academic debate on financial incentives for behaviour change but also policy-makers who consider using financial incentives to change behaviour.

Spatial-Temporal Mapping Reveals the Golgi as the Major Processing Site for the Pathogenic Swedish APP Mutation: Familial APP Mutant Shifts the Major APP Processing Site.

Alzheimer's disease is associated with increased levels of amyloid beta (Aß) generated by sequential intracellular cleavage of amyloid precursor protein (APP) by membrane-bound secretases. However, the spatial and temporal APP cleavage events along the trafficking pathways are poorly defined. Here, we use the Retention Using Selective Hooks (RUSH) to compare in real time the anterograde trafficking and temporal cleavage events of wild-type APP (APPwt) with the pathogenic Swedish APP (APPswe) and the disease-protective Icelandic APP (APPice). The analyses revealed differences in the trafficking profiles and processing between APPwt and the APP familial mutations. While APPwt was predominantly processed by the ß-secretase, BACE1, following Golgi transport to the early endosomes, the transit of APPswe through the Golgi was prolonged and associated with enhanced amyloidogenic APP processing and Aß secretion. A 20°C block in cargo exit from the Golgi confirmed ß- and γ-secretase processing of APPswe in the Golgi. Inhibition of the ß-secretase, BACE1, restored APPswe anterograde trafficking profile to that of APPwt. APPice was transported rapidly through the Golgi to the early endosomes with low levels of Aß production. This study has revealed different intracellular locations for the preferential cleavage of APPwt and APPswe and Aß production, and the Golgi as the major processing site for APPswe, findings relevant to understand the molecular basis of Alzheimer's disease.

Cystatin C-Based Equation to Estimate GFR without the Inclusion of Race and Sex.

BACKGROUND: The accuracy of estimation of kidney function with the use of routine metabolic tests, such as measurement of the serum creatinine level, has been controversial. The European Kidney Function Consortium (EKFC) developed a creatinine-based equation (EKFC eGFRcr) to estimate the glomerular filtration rate (GFR) with a rescaled serum creatinine level (i.e., the serum creatinine level is divided by the median serum creatinine level among healthy persons to control for variation related to differences in age, sex, or race). Whether a cystatin C-based EKFC equation would increase the accuracy of estimated GFR is unknown. METHODS: We used data from patients in Sweden to estimate the rescaling factor for the cystatin C level in adults. We then replaced rescaled serum creatinine in the EKFC eGFRcr equation with rescaled cystatin C, and we validated the resulting EKFC eGFRcys equation in cohorts of White patients and Black patients in Europe, the United States, and Africa, according to measured GFR, levels of serum creatinine and cystatin C, age, and sex. RESULTS: On the basis of data from 227,643 patients in Sweden, the rescaling factor for cystatin C was estimated at 0.83 for men and women younger than 50 years of age and 0.83 + 0.005 × (age - 50) for those 50 years of age or older. The EKFC eGFRcys equation was unbiased, had accuracy that was similar to that of the EKFC eGFRcr equation in both White patients and Black patients (11,231 patients from Europe, 1093 from the United States, and 508 from Africa), and was more accurate than the Chronic Kidney Disease Epidemiology Collaboration eGFRcys equation recommended by Kidney Disease: Improving Global Outcomes. The arithmetic mean of EKFC eGFRcr and EKFC eGFRcys further improved the accuracy of estimated GFR over estimates from either biomarker equation alone. CONCLUSIONS: The EKFC eGFRcys equation had the same mathematical form as the EKFC eGFRcr equation, but it had a scaling factor for cystatin C that did not differ according to race or sex. In cohorts from Europe, the United States, and Africa, this equation improved the accuracy of GFR assessment over that of commonly used equations. (Funded by the Swedish Research Council.).

Increased risk of venous thromboembolism in young and middle-aged individuals with hereditary angioedema: a family study.

ABSTRACT: Hereditary angioedema (HAE), caused by C1 inhibitor protein deficiency, was recently shown to be associated with an increased risk for venous thromboembolism (VTE). To our knowledge, this is the first national family study of HAE, which aimed to determine the familial risk of VTE. The Swedish Multi-Generation Register was linked to the Swedish National Patient Register for the period of 1964 to 2018. Only patients with HAE with a validated diagnosis were included in the study and were linked to their family members. Hazard ratios (HRs) and 95% confidence intervals (CIs) for VTE were calculated for patients with HAE in comparison with relatives without HAE. Among 2006 individuals (from 276 pedigrees of 365 patients with HAE), 103 individuals were affected by VTE. In total, 35 (9.6%) patients with HAE were affected by VTE, whereas 68 (4.1%) non-HAE relatives were affected (P < .001). The adjusted HR for VTE among patients with HAE was 2.51 (95% CI, 1.67-3.77). Patients with HAE were younger at the first VTE than their non-HAE relatives (mean age, 51 years vs 63 years; P < .001). Before the age of 70 years, the HR for VTE among patients with HAE was 3.62 (95% CI, 2.26-5.80). The HR for VTE for patients with HAE born after 1964 was 8.29 (95% CI, 2.90-23.71). The HR for VTE for patients with HAE who were born in 1964 or earlier was 1.82 (95% CI, 1.14-2.91). HAE is associated with VTE among young and middle-aged individuals in Swedish families with HAE. The effect size of the association is in the order of other thrombophilias. We suggest that HAE may be considered a new rare thrombophilia.

Malignancy-associated hemophagocytic lymphohistiocytosis in Sweden: incidence, clinical characteristics, and survival.

ABSTRACT: We evaluated malignancy-associated hemophagocytic lymphohistiocytosis (mal-HLH) in Sweden regarding population-based incidence, clinical features, and survival. From 1997 to 2018, we identified 307 adults (≥18 years old) and 9 children (209 males, 107 females; P < .001) with both an HLH-related diagnosis and malignant disease, corresponding to 0.19 per 100 000 adults annually (0.15/100 000 for the entire population), increasing from 0.026 (1997-2007) to 0.34 (2008-2018) (P < .001). In the latest 7-year period (2012-2018), the annual incidence was 0.45 per 100 000 adults (n = 246). This incidence varied between the 6 health care regions in Sweden, from 0.18 to 0.71 (Region Stockholm) per 100 000 adults annually (P < .001), likely due to variable awareness. Mal-HLH was reported in 0.6% of all hematological malignancies, with the highest proportion (2.5%) in young males. Among the 316 patients, the 1-month probability of survival, likely representing the HLH episode, increased significantly from 52% (95% confidence interval [CI], 40-63) (1997-2007) to 71% (95% CI, 65-76) (2008-2018), whereas 2-year survival remained poor (25%; 95% CI, 20-30). Altogether, 52% were lymphomas, 29% leukemias, 8% other hematological malignancies, and 11% solid tumors. Males were more affected than females by mal-HLH, also taking the over-representation of males with hematological malignancies into account (P = .0012). Validation by medical-file reviews revealed 13% over-reporting of HLH. We conclude that the annual mal-HLH incidence has increased 10-fold and was at least 0.71 per 100 000 adults from 2012 to 2018, that is, 0.62 per 100 000 adults considering 13% estimated HLH over-reporting, and that early survival improved significantly, likely due to increased awareness and more HLH-directed therapy.

Inequality and COVID-19 in Sweden: Relative risks of nine bad life events, by four social gradients, in pandemic vs. prepandemic years.

The COVID-19 pandemic struck societies directly and indirectly, not just challenging population health but disrupting many aspects of life. Different effects of the spreading virus-and the measures to fight it-are reported and discussed in different scientific fora, with hard-to-compare methods and metrics from different traditions. While the pandemic struck some groups more than others, it is difficult to assess the comprehensive impact on social inequalities. This paper gauges social inequalities using individual-level administrative data for Sweden's entire population. We describe and analyze the relative risks for different social groups in four dimensions-gender, education, income, and world region of birth-to experience three types of COVID-19 incidence, as well as six additional negative life outcomes that reflect general health, access to medical care, and economic strain. During the pandemic, the overall population faced severe morbidity and mortality from COVID-19 and saw higher all-cause mortality, income losses and unemployment risks, as well as reduced access to medical care. These burdens fell more heavily on individuals with low income or education and on immigrants. Although these vulnerable groups experienced larger absolute risks of suffering the direct and indirect consequences of the pandemic, the relative risks in pandemic years (2020 and 2021) were conspicuously similar to those in prepandemic years (2016 to 2019).

Excess Mortality and Loss of Life Expectancy After Myocardial Infarction: A Registry-Based Matched Cohort Study.

BACKGROUND: The effect of myocardial infarction (MI) on life expectancy is difficult to study because the prevalence of MI hinders direct comparison with the life expectancy of the general population. We sought to assess this in relation to age, sex, and left ventricular ejection fraction (LVEF) by comparing individuals with MI with matched comparators without previous MI. METHODS: We included patients with a first MI between 1991 and 2022 from the nationwide SWEDEHEART registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies), each matched with up to 5 comparators on age, sex, and region of residence. Flexible parametric survival models were used to estimate excess mortality and mean loss of life expectancy (LOLE) depending on index year, age, sex, and LVEF, and adjusted for differences in characteristics. RESULTS: A total of 335 748 cases were matched to 1 625 396 comparators. A higher LOLE was observed in younger individuals, women, and those with reduced LVEF (<50%). In 2022, the unadjusted and adjusted mean LOLE spanned from 11.1 and 9.5 years in 50-year-old women with reduced LVEF to 5 and 3.7 months in 80-year-old men with preserved LVEF. Between 1992 and 2022, the adjusted mean LOLE decreased by 36% to 55%: from 4.4 to 2.0 years and from 3.3 to 1.9 years in 50-year-old women and men, respectively, and from 1.7 to 1.0 years and from 1.4 to 0.9 years in 80-year-old women and men, respectively. CONCLUSIONS: LOLE is higher in younger individuals, women, and those with reduced LVEF, but is attenuated when adjusting for comorbidities and risk factors. Advances in MI treatment during the past 30 years have almost halved LOLE, with no clear sign of leveling off to a plateau.

Historic dog Furs Unravel the Origin and Artificial Selection of Modern Nordic Lapphund and Elkhound dog Breeds.

The origins and extreme morphological evolution of the modern dog breeds are poorly studied because the founder populations are extinct. Here, we analyse eight 100 to 200 years old dog fur samples obtained from traditional North Swedish clothing, to explore the origin and artificial selection of the modern Nordic Lapphund and Elkhound dog breeds. Population genomic analysis confirmed the Lapphund and Elkhound breeds to originate from the local dog population, and showed a distinct decrease in genetic diversity in agreement with intense breeding. We identified eleven genes under positive selection during the breed development. In particular, the MSRB3 gene, associated with breed-related ear morphology, was selected in all Lapphund and Elkhound breeds, and functional assays showed that a SNP mutation in the 3'UTR region suppresses its expression through miRNA regulation. Our findings demonstrate analysis of near-modern dog artifacts as an effective tool for interpreting the origin and artificial selection of the modern dog breeds.

First dose of misoprostol administration at home or in hospital for medical abortion between 12-22 gestational weeks in Sweden (PRIMA): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Medical abortion after 12 gestational weeks often requires a stay in hospital. We hypothesised that administering the first misoprostol dose at home could increase day-care procedures as compared with overnight care procedures, shorten inpatient stays, and improve patient satisfaction. METHODS: This multicentre, open-label, randomised controlled trial was done at six hospitals in Sweden. Participants were pregnant people aged 18 years and older who were undergoing medical abortion at 85-153 days of pregnancy. Randomisation was done in blocks 1:1 to mifepristone administered in-clinic followed by home administration or hospital administration of the first dose of misoprostol. Allocation was done by opening of opaque allocation envelopes. Due to the nature of the intervention, masking was not feasible. Between 24-48 h after mifepristone 200 mg, the participants administered 800 µg of misoprostol either at home 2 h before admission to hospital or in hospital. The primary outcome was the proportion of day-care procedures (defined as abortion completed in <9 h). The intention-to-treat analysis included all participants randomly assigned to receive the study drug and who had known results for the primary outcome. Individuals who received any treatment were included in the safety analyses. This trial is registered at ClinicalTrials.gov, NTC03600857, and EudraCT, 2018-000964-27. FINDINGS: Between Jan 8, 2019, and Dec 21, 2022, 457 participants were randomly assigned to treatment groups. In the intention-to-treat-population, 220 participants were assigned to the home group and 215 to the hospital group. In the home group, 156 (71%) of 220 participants completed the abortion as day-care patients, compared with 99 (46%) of 215 in the hospital group (difference 24·9%, 95% CI 15·4-34·3; p<0·0001). In total, 97 (22%) of 444 participants in the safety analysis had an adverse event. Seven (2%) of 444 participants aborted after mifepristone only. Two (1%) of 220 in the home group aborted after the first dose of misoprostol, before hospital admission. INTERPRETATION: Home administration of misoprostol significantly increases the proportion of day-care procedures in medical abortion after 12 gestational weeks, offering a safe and effective alternative to in-clinic protocols. FUNDING: Region Västra Götaland, Hjalmar Svensson's Fund, the Gothenburg Society of Medicine, Karolinska Institutet-Region Stockholm, and The Swedish Research Council.

Rates and causes of death after release from incarceration among 1 471 526 people in eight high-income and middle-income countries: an individual participant data meta-analysis.

BACKGROUND: Formerly incarcerated people have exceptionally poor health profiles and are at increased risk of preventable mortality when compared with their general population peers. However, not enough is known about the epidemiology of mortality in this population-specifically the rates, causes, and timing of death in specific subgroups and regions-to inform the development of targeted, evidence-based responses. We aimed to document the incidence, timing, causes, and risk factors for mortality after release from incarceration. METHODS: We analysed linked administrative data from the multi-national Mortality After Release from Incarceration Consortium (MARIC) study. We examined mortality outcomes for 1 471 526 people released from incarceration in eight countries (Australia, Brazil, Canada, New Zealand, Norway, Scotland, Sweden, and the USA) from 1980 to 2018, across 10 534 441 person-years of follow-up (range 0-24 years per person). We combined data from 18 cohort studies using two-step individual participant data meta-analyses to estimate pooled all-cause and cause-specific crude mortality rates (CMRs) per 100 000 person-years, for specific time periods (first, daily from days 1-14; second, weekly from weeks 3-12; third, weeks 13-52 combined; fourth, weeks 53 and over combined; and fifth, total follow-up) after release, overall and stratified by age, sex, and region. FINDINGS: 75 427 deaths were recorded. The all-cause CMR during the first week following release (1612 [95% CI 1048-2287]) was higher than during all other time periods (incidence rate ratio [IRR] compared with week 2: 1·5 [95% CI 1·2-1·8], I2=26·0%, weeks 3-4: 2·0 [1·5-2·6], I2=53·0%, and weeks 9-12: 2·2 [1·6-3·0], I2=70·5%). The highest cause-specific mortality rates during the first week were due to alcohol and other drug poisoning (CMR 657 [95% CI 332-1076]), suicide (135 [36-277]), and cardiovascular disease (71 [16-153]). We observed considerable variation in cause-specific CMRs over time since release and across regions. Pooled all-cause CMRs were similar between males (731 [95% CI 630-839]) and females (660 [560-767]) and were higher in older age groups. INTERPRETATION: The markedly elevated rate of death in the first week post-release underscores an urgent need for investment in evidence-based, coordinated transitional healthcare, including treatment for mental illness and substance use disorders to prevent post-release deaths due to suicide and overdose. Temporal variations in rates and causes of death highlight the need for routine monitoring of post-release mortality. FUNDING: Australia's National Health and Medical Research Council.

Histologic Remission in Inflammatory Bowel Disease and Female Fertility: A Nationwide Study.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is linked to reduced female fertility, but it is unclear how fertility rates vary by histologic disease activity. METHODS: Nationwide IBD cohort of Swedish women aged 15 to 44 years. We examined fertility rates during periods with vs without histologic inflammation (n = 21,046; follow-up, 1990-2016) and during periods with vs without clinical activity (IBD-related hospitalization, surgery, or treatment escalation) (n = 24,995; follow-up, 2006-2020). Accounting for sociodemographics and comorbidities, we used Poisson regression to estimate adjusted fertility rate ratios (aFRRs) for live births conceived during 12-month periods of histologic inflammation (vs histologic remission) and 3-month periods of clinically active IBD (vs quiescent IBD). RESULTS: During periods with vs without histologic inflammation, there were 6.35 (95% confidence interval [CI], 5.98-6.73) and 7.09 (95% CI, 6.48-7.70) live births conceived per 100 person-years of follow-up, respectively, or 1 fewer child per 14 women with 10 years of histologic inflammation (aFRR, 0.90; 95% CI, 0.81-1.00). In women with histologic inflammation, fertility was similarly reduced in ulcerative colitis (UC) (aFRR, 0.89 [95% CI, 0.78-1.02]) and Crohn's disease (CD) (aFRR, 0.86 [95% CI, 0.72-1.04]). Clinical IBD activity was associated with an aFRR of 0.76 (95% CI, 0.72-0.79) or 1 fewer child per 6 women with 10 years of clinical activity. Fertility was reduced in clinically active UC (aFRR, 0.75 [95% CI, 0.70-0.81]) and CD (aFRR, 0.76 [95% CI, 0.70-0.82]). Finally, among women with clinically quiescent IBD, histologic inflammation (vs histologic remission) was associated with reduced fertility (aFRR, 0.85 [95% CI, 0.73-0.98]). CONCLUSIONS: An association between histologic and clinical activity and reduced female fertility in CD and UC was found. Notably, histologic inflammation was also linked to reduced fertility in women with clinically quiescent IBD.

HLA Associations of Intrathecal IgG Production against Specific Viruses in Multiple Sclerosis.

OBJECTIVE: Specific human leucocyte antigen (HLA) alleles are not only associated with higher risk to develop multiple sclerosis (MS) and other autoimmune diseases, but also with the severity of various viral and bacterial infections. Here, we analyzed the most specific biomarker for MS, that is, the polyspecific intrathecal IgG antibody production against measles, rubella, and varicella zoster virus (MRZ reaction), for possible HLA associations in MS. METHODS: We assessed MRZ reaction from 184 Swiss patients with MS and clinically isolated syndrome (CIS) and 89 Swiss non-MS/non-CIS control patients, and performed HLA sequence-based typing, to check for associations of positive MRZ reaction with the most prevalent HLA alleles. We used a cohort of 176 Swedish MS/CIS patients to replicate significant findings. RESULTS: Whereas positive MRZ reaction showed a prevalence of 38.0% in MS/CIS patients, it was highly specific (97.7%) for MS/CIS. We identified HLA-DRB1*15:01 and other tightly linked alleles of the HLA-DR15 haplotype as the strongest HLA-encoded risk factors for a positive MRZ reaction in Swiss MS/CIS (odds ratio [OR], 3.90, 95% confidence interval [CI] 2.05-7.46, padjusted = 0.0004) and replicated these findings in Swedish MS/CIS patients (OR 2.18, 95%-CI 1.16-4.02, padjusted = 0.028). In addition, female MS/CIS patients had a significantly higher probability for a positive MRZ reaction than male patients in both cohorts combined (padjusted <0.005). INTERPRETATION: HLA-DRB1*15:01, the strongest genetic risk factor for MS, and female sex, 1 of the most prominent demographic risk factors for developing MS, predispose in MS/CIS patients for a positive MRZ reaction, the most specific CSF biomarker for MS. ANN NEUROL 2024;95:1112-1126.

Real-World Healthcare Cost Savings and Reduced Relapse Rate with Off-Label Rituximab versus Disease-Modifying Treatments Approved for Relapsing-Remitting Multiple Sclerosis: A Nationwide Cost-Effectiveness Study.

OBJECTIVE: Although off-label use of rituximab is a common alternative to disease-modifying therapies (DMTs) approved for multiple sclerosis (MS) in several countries, the impact of this on treatment cost-effectiveness is not well known. METHODS: We evaluated the relative cost-effectiveness of rituximab and MS-approved DMTs in a register-based cohort study of Swedish residents with relapsing-remitting MS, aged 18-65 years, starting treatment with rituximab, natalizumab, fingolimod, or dimethyl fumarate between January 2010 and July 2016, and followed through July 2021 (n = 5,924). By linking the population-based Swedish MS register to several Swedish health care and demographic registers, we estimated health care costs in relation to number of relapses, over 5 years from treatment start. Differences between treatments were estimated in inverse probability of treatment-weighted regression models, adjusting for a broad range of potential confounders covering demographics, medical history, and MS-related clinical characteristics. RESULTS: Off-label rituximab was associated with both lower total health care costs (mean cost savings ranged $35,000-$66,000 vs. each approved DMT), and fewer relapses (mean number of prevented relapses ranged 0.12-0.22), per started therapy over 5 years. Results were robust to variations in discounting and pricing of health care visits, with the main driver of cost-savings being the price of the index drug itself. INTERPRETATION: The cost-effectiveness of rituximab dominated the MS-approved alternatives. Off-label, low-dose rituximab should be considered for persons with MS and could reduce barriers to treatment, especially in resource-limited settings. ANN NEUROL 2024;95:1099-1111.

Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population.

While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13-38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10-5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33-43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

Bidirectional association between autoimmune disease and perinatal depression: a nationwide study with sibling comparison.

Although major depression, characterized by a pro-inflammatory profile, genetically overlap with autoimmune disease (AD) and the perinatal period involve immune system adaptations and AD symptom alterations, the bidirectional link between perinatal depression (PND) and AD is largely unexplored. Hence, the objective of this study was to investigate the bidirectional association between PND and AD. Using nationwide Swedish population and health registers, we conducted a nested case-control study and a matched cohort study. From 1,347,901 pregnancies during 2001-2013, we included 55,299 incident PND, their unaffected full sisters, and 10 unaffected matched women per PND case. We identified 41 subtypes of AD diagnoses recorded in the registers and compared PND with unaffected population-matched women and full sisters, using multivariable regressions. Women with an AD had a 30% higher risk of subsequent PND (95% CI 1.2-1.5) and women exposed to PND had a 30% higher risk of a subsequent AD (95% CI 1.3-1.4). Comparable associations were found when comparing exposed women with their unaffected sisters (nested case-control OR: 1.3, 95% CI 1.2-1.5, matched cohort HR: 1.3, 95% CI 1.1-1.6), and when studying antepartum and postpartum depression. The bidirectional association was more pronounced among women without psychiatric comorbidities (nested case-control OR: 1.5, 95% CI 1.4-1.6, matched cohort HR: 1.4, 95% CI 1.4-1.5) and strongest for multiple sclerosis (nested case-control OR: 2.0, 95% CI 1.6-2.3, matched cohort HR: 1.8, 95% CI 1.0-3.1). These findings demonstrate a bidirectional association between AD and PND independent of psychiatric comorbidities, suggesting possibly shared biological mechanisms. If future translational science confirms the underlying mechanisms, healthcare providers need to be aware of the increased risk of PND among women with ADs and vice versa.

Key subphenotypes of bipolar disorder are differentially associated with polygenic liabilities for bipolar disorder, schizophrenia, and major depressive disorder.

Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N = 5180) and the UK (N = 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRS but negatively correlated with schizophrenia-PRS (SCZ-PRS) and MDD-PRS. Moreover, BD-PRS was negatively, and MDD-PRS positively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRS was positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment.

The relationship between familial-genetic risk and pharmacological treatment in a Swedish national sample of patients with major depression, bipolar disorder, and schizophrenia.

Using Swedish registers, we examine whether the prescription of and the response to antidepressants (AD), mood stabilizers (MS), and antipsychotics (AP) in the treatment of, respectively, major depression (MD), bipolar disorder (BD), and schizophrenia (SZ), are influenced by familial-genetic risk. We examined individuals born in Sweden 1960-1995 with a first diagnosis of MD (n = 257,177), BD (n = 23,032), and SZ (n = 4248) from 2006 to 2018. Drug classes and Defined Daily Dose (DDD) were obtained from the Pharmacy register using the Anatomical Therapeutic Chemical system. We utilized the Familial Genetic Risk Scores (FGRS) calculated from morbidity risks in first- through fifth degree relatives. Treatment with antidepressants (AD) in MD, mood-stabilizers (MS) in BD, and antipsychotics (AP) in SZ were associated with significantly higher disorder-specific familial-genetic risks. Using dosage trajectory analysis of AD, MS, and AP treatment for MD, BD, and SZ, respectively, familial-genetic risk was positively associated with higher and/or increasing drug dosages over time. For MD and BD, examining cases started on the most common pharmacologic treatment class (SSRIs for MD and "other anti-epileptics" for BD), familial-genetic risks were significantly lower in those who did not versus did later receive treatment from other AD and MS classes, respectively. Higher familial-genetic risk for BD predicted switching AD medication in cases of MD. Among pharmacologically treated cases of BD, familial-genetic risk was significantly higher for those treated with lithium. In a large population-based patient cohort, we found evidence of a wide-spread association between higher familial-genetic risk and i) increased likelihood of receiving pharmacologic treatment but 2) responding more poorly to it-as indicated by a switching of medications -- and/or requiring higher doses. Further investigations into the clinical utility of genetic risk scores in the clinical managements of MD, BD, and SZ are warranted.

Lipidomic risk scores are independent of polygenic risk scores and can predict incidence of diabetes and cardiovascular disease in a large population cohort.

Type 2 diabetes (T2D) and cardiovascular disease (CVD) represent significant disease burdens for most societies and susceptibility to these diseases is strongly influenced by diet and lifestyle. Physiological changes associated with T2D or CVD, such has high blood pressure and cholesterol and glucose levels in the blood, are often apparent prior to disease incidence. Here we integrated genetics, lipidomics, and standard clinical diagnostics to assess future T2D and CVD risk for 4,067 participants from a large prospective population-based cohort, the Malmö Diet and Cancer-Cardiovascular Cohort. By training Ridge regression-based machine learning models on the measurements obtained at baseline when the individuals were healthy, we computed several risk scores for T2D and CVD incidence during up to 23 years of follow-up. We used these scores to stratify the participants into risk groups and found that a lipidomics risk score based on the quantification of 184 plasma lipid concentrations resulted in a 168% and 84% increase of the incidence rate in the highest risk group and a 77% and 53% decrease of the incidence rate in lowest risk group for T2D and CVD, respectively, compared to the average case rates of 13.8% and 22.0%. Notably, lipidomic risk correlated only marginally with polygenic risk, indicating that the lipidome and genetic variants may constitute largely independent risk factors for T2D and CVD. Risk stratification was further improved by adding standard clinical variables to the model, resulting in a case rate of 51.0% and 53.3% in the highest risk group for T2D and CVD, respectively. The participants in the highest risk group showed significantly altered lipidome compositions affecting 167 and 157 lipid species for T2D and CVD, respectively. Our results demonstrated that a subset of individuals at high risk for developing T2D or CVD can be identified years before disease incidence. The lipidomic risk, which is derived from only one single mass spectrometric measurement that is cheap and fast, is informative and could extend traditional risk assessment based on clinical assays.