Association of obesity to reaction time and visual memory in schizophrenia.

Background: Both overweight and cognitive deficits are common among people with schizophrenia (SZ) and schizoaffective disorder. The results in earlier studies have been inconsistent on whether overweight is associated with cognitive deficits in psychotic disorders. Aims: Our aim in this study was to detect possible associations between obesity and cognitive deficits among study participants with SZ and schizoaffective disorder. Methods: The study sample included 5382 participants with a clinical diagnosis of SZ or schizoaffective disorder selected from the Finnish SUPER study. Obesity was measured both with body-mass index and waist circumference. The cognitive performance was evaluated with two tests from the Cambridge automated neuropsychological test battery: Reaction time was evaluated with the 5-choice serial reaction time task. Visual memory was evaluated with the paired associative learning test. The final analysis included a total sample of 4498 participants applicable for the analysis of the reaction time and 3967 participants for the analysis of the visual memory. Results: Obesity measured with body-mass index was associated with better performance in reaction time task among both female and male participants. Among male participants, overweight was associated with better performance in the visual memory test. The waist circumference was not associated with cognitive measures. Conclusions: The results suggest that obesity in people with SZ or schizoaffective disorder might not be associated with cognitive deficits but instead with better cognitive performance. The results were opposite from earlier literature on the general population. More research is required to better understand whether the results might be partly caused by the differences in the etiology of obesity between the general population and people with SZ.

Use of antipsychotics and antidepressants in first-episode psychotic depression: A nationwide register-based study.

BACKGROUND: According to guidelines, psychotic depression should be treated with both antipsychotics and antidepressants, but current practice is largely unknown. We investigated the prevalence of antipsychotic and antidepressant use in first-episode psychotic depression and factors related to antipsychotic use after the diagnosis. METHODS: We identified individuals aged 16-65 with a first-episode diagnosis of psychotic depression (ICD-10 codes F32.3, F33.3) from nationwide data linkage of Finnish healthcare and population registers during 2000-2018. Point prevalence was measured as 2-week time windows every 3 months, investigating whether the individual had a modeled drug use period ongoing during the window or not, censoring to death and end of data linkage. RESULTS: The study population included 18,490 individuals (58.0% women; mean age 39.9 years, standard deviation 14.7). The prevalence of use for antidepressants (75.0%), antipsychotics (56.4%), and both (50.0%) were highest at 3 months after the diagnosis. The prevalence declined to 51.8%, 34.1%, and 28.7%, respectively, at 3 years after the diagnosis. In a logistic regression analysis, younger age (adjusted odds ratio < 25 vs. ≥55, 0.82 [95% confidence interval 0.73-0.91]), eating disorders (0.78 [0.66-0.92]), substance use disorders (0.80 [0.73-0.87]), and occupational inactivity (0.80 [0.73-0.87]) were associated with decreased odds of using antipsychotics at 3 months after diagnosis. Increased odds were found for diagnosis from inpatient care (1.74 [1.62-1.86]), and later year of cohort entry (2010-2014 vs. 2000-2004, 1.56 [1.42-1.70]). CONCLUSION: At most, half of the individuals with newly diagnosed psychotic depression used both antidepressants and antipsychotics. This likely has a negative impact on treatment success.

Comparative effectiveness of mood stabilizers and antipsychotics in the prevention of hospitalization after lithium discontinuation in bipolar disorder.

The aim of the study was to compare the real-world effectiveness of mood stabilizers and antipsychotics in the prevention of psychiatric hospitalizations and treatment failure after lithium discontinuation in a nationwide bipolar cohort. Using health-care registers, we identified everyone in Finland diagnosed with bipolar disorder during 1987-2018 who discontinued lithium after using it for at least one year (n = 4 052, median period of lithium use before discontinuation 2.7 years). The risk of psychiatric hospitalization and treatment failure (psychiatric hospitalization, death or change in medication) were investigated with within-individual Cox regression. Of mood stabilizer monotherapies, the periods of valproate use (HR = 0.83, 95% CI = 0.71 - 0.97) had lower risk of hospitalization than nonuse of mood stabilizers. Of antipsychotic monotherapies, the use of long-acting injectable (LAI) antipsychotics (HR = 0.48, 95% CI = 0.26 - 0.88) and chlorprothixene (HR = 0.62, 95% CI = 0.44 - 0.88) were associated with lower risk and the use of quetiapine (HR = 1.26, 95% CI = 1.07 - 1.48) and oral olanzapine (HR = 1.23, 95% CI = 1.01 - 1.49) with higher risk of psychiatric hospitalizations than nonuse of antipsychotics. Of mood stabilizer monotherapies, lithium use was associated with lower risk of treatment failure (HR = 0.82, 95% CI = 0.76 - 0.88) than valproate use. The results suggest that antipsychotic LAIs are especially effective in the prevention of psychiatric hospitalizations after lithium discontinuation. The need to alter used medications may be the lowest when lithium is restarted.

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

Risk of labour market marginalisation among young refugees and non-refugee migrants with common mental disorders.

PURPOSE: Labour market marginalisation (LMM), i.e. long-term unemployment (LTU), long-term sickness absence (LTSA) and disability pension (DP), among young individuals with common mental disorders (CMDs) are a challenge for the welfare system, and refugees and non-refugee migrants seem particularly vulnerable. The aim was to investigate the risk of LMM in young adults with CMDs among refugees and non-refugee migrants compared to Swedish-born individuals and the role of country of birth, duration of residence and age at arrival. METHODS: A prospective cohort study was conducted including young adults (19-30 years) with inpatient or specialised outpatient healthcare due to CMDs and/or antidepressant prescriptions during 2009 (N = 69,515). Cox regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals for the risk of LMM during 2010-2013. RESULTS: Both refugees and non-refugee migrants had a higher risk of LTU compared to Swedish-born individuals (HR refugees: Africa: 2.4; Asia: 2.2; Europe outside EU25: 1.6; South America: 1.4) with highest estimates in refugees from Afghanistan and Syria. Refugees from Africa and Asia had a lower risk of LTSA compared to Swedish-born individuals (HR: 0.6 and 0.7, respectively), particularly refugees from Afghanistan and Iraq. Especially among refugees, a longer duration of residence and a younger age at arrival were associated with a lower risk of LTU. CONCLUSIONS: The risk of LTU among refugees and non-refugee migrants was higher and the risk of LTSA was lower, compared to Swedish-born individuals. Duration of residence and age at arrival had an influence on the risk of LTU, particularly among refugees.

Detection of medications associated with Alzheimer's disease using ensemble methods and cooperative game theory.

OBJECTIVE: To study the feasibility of evaluating feature importance with Shapley Values and ensemble methods in the context of pharmacoepidemiology and medication safety. METHODS: We detected medications associated with Alzheimer's disease (AD) by examining the additive feature attribution with combined approach of Gradient Boosting and Shapley Values in the Medication use and Alzheimer's disease (MEDALZ) study, a nested case-control study of 70,719 verified AD cases in Finland. Our methodological approach is to do binary classification using Gradient boosting (an ensemble of weak classifiers) in a supervised learning manner. Then we apply Shapley Values (from cooperative game theory) to analyze how feature combinations affect the classification result. Medication use with a five to one year time-window before AD diagnosis was ascertained from Prescription register. RESULTS: Antipsychotics with low or medium dose, antidepressants with medium to high dose, and cardiovascular medications with medium to high dose were identified as the contributing features for separating cases with AD from controls. Medium to high amount of irregularity in the purchase pattern were an indicating feature for separating AD cases from controls. The similarity of medication purchases between AD cases and controls made the feature evaluation challenging. CONCLUSIONS: The combined approach of Gradient Boosting and feature evaluation with Shapley Values identified features that were consistent with findings from previous hypothesis-driven studies. Additionally, the results from the additive feature attribution identified new candidates for future studies on AD risk factors. Our approach also shows promise for studies based on observational studies, where feature identification and interactions in populations are of interest; and the applicability of using Shapley Values for evaluating feature relevance in pattern recognition tasks.

Trajectories of sickness absence, disability pension and unemployment in young immigrants with common mental disorders.

BACKGROUND: The aims were to elucidate if trajectories of labour market marginalization (LMM), measured as sickness absence (SA)/disability pension (DP) or unemployment, differed between young immigrants and natives before and after an incident diagnosis of a common mental disorder (CMD), and to investigate if educational level, psychiatric comorbidity and duration of residence in Sweden (in immigrants) had different associations with subsequent LMM in natives compared with immigrants. METHODS: A total of 28 971 young adults (19-30 years), with an incident CMD (inpatient or specialized outpatient healthcare due to CMDs or dispensed prescribed antidepressants during 2007) were included. Group-based trajectory models were utilized to identify trajectories of annual months of LMM 3 years before and 6 years after the diagnosis. The associations of risk factors with different trajectories were investigated by multinomial logistic regression, χ2-test and Nagelkerke R2 to measure the associations' strength. Immigrants were categorized into Western and non-Western immigrants. RESULTS: Young natives and immigrants showed similar trajectories of SA/DP. A higher proportion of non-Western immigrants (20.5%) followed trajectories of high levels of unemployment (>2 annual months) compared with Western immigrants (15%) and natives (16.5%). Educational level and duration of residence in Sweden (in immigrants) discriminated trajectories of both SA/DP and unemployment, whereas psychiatric comorbidity only discriminated trajectories of SA/DP. CONCLUSIONS: Differences in trajectories of unemployment between young natives and immigrants with an incident CMD were found. Educational level and psychiatric comorbidity provided information on differences between natives and immigrants and duration of residence gave information for subgroups of immigrants.

Long-term thiazide use and risk of low-energy fractures among persons with Alzheimer's disease-nested case-control study.

We investigated the association between thiazide use and the risk of low-energy fractures among community dwellers with Alzheimer's disease. Longer use was associated with a decreased risk of low-energy fractures. This study extends the previous knowledge of reduced fracture risk of thiazides to persons with Alzheimer's disease. INTRODUCTION: To investigate the association between thiazide use and the risk of low-energy fractures (LEF), and hip fracture among community dwellers with Alzheimer's disease (AD). No prior study has evaluated the effect of thiazides on LEF risk of AD patients. METHODS: LEF cases were identified from the MEDALZ study, including all community-dwelling persons diagnosed with AD in Finland 2005-2011. During the follow-up from AD diagnoses until the end of 2015, cases with LEF (N = 10,416) and hip fracture (N = 5578) were identified. LEF cases were matched with up to three controls without LEF, according to time since AD diagnosis, age and gender. Thiazide use identified from the Prescription register data was modeled with PRE2DUP method. Current use was defined in 0-30 days' time window before the fracture/matching date, and duration of current use was assessed. The association between thiazide exposure and LEFs was assessed with conditional logistic regression. RESULTS: Current thiazide use was observed in 10.5% of LEF cases and 12.5% of controls. Current thiazide use was associated with a decreased risk of LEF (adjusted OR [aOR] 0.83, 95% CI 0.77-0.88). In terms of the duration of use, no association was observed with short-term use (< 1 year or 1-3 years), while longer use (> 3 years) was associated with a reduced risk of LEF (aOR 0.77, 95% CI 0.71-0.83) and hip fracture (aOR 0.68, 95% CI 0.60-0.78). CONCLUSIONS: Our study extends the previous knowledge of reduced fracture risk of thiazides to persons with AD, a population with significantly increased background risk of fractures.

The risk of Alzheimer's disease associated with benzodiazepines and related drugs: a nested case-control study.

OBJECTIVE: To assess the association between benzodiazepine and related drug (BZDR) use and risk of Alzheimer's disease (AD) with cumulative consumption and duration of use based models. METHOD: A nationwide nested case-control study of all Finnish community-dwelling persons who received clinically verified AD diagnosis in 2005-2011 (N = 70 719) and their matched controls (N = 282 862). AD diagnosis was based on DSM-IV and NINCDS-ADRDA criteria. BZDR purchases were extracted from the Prescription Register since 1995. The association between BZDR use and AD was assessed using conditional logistic regression with 5-year lag time between exposure and outcome. RESULTS: Benzodiazepine and related drug use was associated with modestly increased risk of AD (adjusted OR 1.06, 95% CI 1.04-1.08). A dose-response relationship was observed with both cumulative consumption and duration. Adjustment for other psychotropics removed the cumulative dose-response relationship by attenuating the ORs in the highest dose category. CONCLUSION: Benzodiazepine and related drug use in general was associated with modestly increased risk of AD. No major differences were observed between different subcategories of BZDRs (i.e. benzodiazepines, Z drugs, short-/medium-acting or long-acting BZDRs). As dose-response relationship abolished after adjustment for other psychotropics, it is possible that the association may partially be due to antidepressants and/or antipsychotics, or concomitant use of these medications.

Mortality in schizophrenia: 30-year nationwide follow-up study.

OBJECTIVE: Recent reports suggest that the mortality gap between persons with schizophrenia and the general population is increasing. We investigated the mortality, age at death, and causes of death among persons diagnosed with schizophrenia and the general population in Finland during 1984-2014. METHODS: All persons with schizophrenia in Finland were identified from hospital discharge register, and compared with the Finnish population aged 16 years and older during 1984-2014, based on data from Statistics Finland. Age at death and standardized mortality ratio (SMR) were calculated for each follow-up year. RESULTS: Mean age at death increased from 57.6 years in 1984 to 70.1 years in 2014 in persons with schizophrenia, and from 70.9 to 77.5 years in the general population. All-cause SMR remained stable during the follow-up (2.6 in 1984 and 2.7 in 2014). A major change was observed in SMR for suicides which decreased from 11.0 in 1984 to 6.6 in 2014 (-40%). The SMRs for cardiovascular and cancer deaths showed increasing trends. CONCLUSION: The longevity of persons with schizophrenia is improving at approximately the same rate as the general population but suicide rates have declined substantially. However, there is still a major disparity in mortality compared with general population.

Proton pump inhibitor use and risk of hip fractures among community-dwelling persons with Alzheimer's disease-a nested case-control study.

BACKGROUND: Hip fractures are a major health concern among older persons with Alzheimer's disease, who usually use many concomitant drugs for several diseases. Evidence of the association between proton pump inhibitor use and risk of hip fracture is contradictory. AIM: To investigate whether the long-term use of proton pump inhibitor is associated with risk of hip fractures among community-dwelling persons with Alzheimer's disease. METHODS: In this nested case-control study, the nationwide MEDALZ data were utilised. Community-dwelling persons with Alzheimer's disease who encountered incident hip fracture (N = 4818; mean age 84.1) were included as cases. Four controls were matched for each case at the date of hip fracture (N = 19 235; mean age 84.0). The association between hip fracture and duration of current PPI use (ongoing use during 0-30 days before the index date), and cumulative duration of use during 10 years before was investigated with conditional logistic regression. RESULTS: Long-term or cumulative proton pump inhibitor use was not associated with an increased risk of hip fracture. Current proton pump inhibitor use was associated with an increased risk of hip fracture (adjusted OR 1.12, 95% CI 1.03-1.22). The risk was increased in short-term current use (<1 year) (adjusted OR 1.23, 95% CI 1.10-1.37). CONCLUSIONS: The increased risk of hip fracture was evident only in short-term proton pump inhibitor use, but no association was found for long-term or cumulative use. Thus, our findings do not support previous assumptions that long-term proton pump inhibitor use would be associated with an increased risk of hip fractures.

Healthcare use among immigrants and natives in Sweden on disability pension, before and after changes of regulations.

Background: There is limited knowledge regarding psychiatric healthcare utilization around the time of granting disability pension (DP) due to common mental disorders (CMD) among immigrants and if this is related to social insurance regulations. The aim was to evaluate patterns of psychiatric healthcare utilization before and after DP due to CMD among immigrants and natives. A second aim was to evaluate if such patterns differed before and after changes in social insurance regulations in Sweden in 2008. Methods: All 28 354 individuals living in Sweden with incident DP due to CMD, before (2005-06; n = 24 298) or after (2009-10; n = 4056) changes in regulations of granting DP, were included. Patterns of psychiatric in- and specialized outpatient healthcare utilization during a 7-year window around DP granting were assessed by Generalized Estimating Equations estimating multivariate adjusted odds ratios (OR) and 95% confidence intervals (CI). Results: Prevalence rates of psychiatric inpatient care were comparable among immigrants and natives, lower in non-Western immigrants (Africa, Asia and South-America). Three years after DP, non-Western immigrants in comparison to natives and Western immigrants had a stronger decrease in inpatient psychiatric healthcare: OR 0.48 (CI 0.38-0.62), 0.76 (0.70-0.83) and 1.01 (0.76-1.34), respectively. After 2008, a strong reduction in outpatient psychiatric healthcare after DP granting was observed, similarly in immigrants and natives. Conclusions: Non-Western immigrants showed a different pattern of inpatient specialized healthcare after DP granting in comparison to natives. After changes in social insurance regulations, the decline in outpatient psychiatric healthcare following DP granting was comparable in immigrants and natives.

Risk of disability pension in first and second generation immigrants: the role of age and region of birth in a prospective population-based study from Sweden.

BACKGROUND: In several countries, immigrants have higher disability pension (DP) rates than natives. Reasons for this are poorly understood. The aim of this study was to investigate if the risk of diagnosis-specific DP differed in first, second, and second/intermediate generation immigrants compared to natives, in general and across regions of birth, and stratified by age. METHODS: A population-based prospective cohort study of all 3,507,055 individuals aged 19-50 years and living in Sweden in 2004 with a 6-year follow-up period. Hazard ratios (HR) and 95% confidence intervals (CI) for mental and somatic DP were estimated by Cox regression for first, second, and second/intermediate generation immigrants compared to natives, across regions of birth and stratified by age. RESULTS: After multivariate adjustment, HRs for both mental and somatic DP were higher at follow-up in the first generation compared to natives: mental HR 1.17 (CI 1.12-1.22) and somatic 1.15 (1.09-1.22) for individuals <35 years; 1.74 (1.69-1.79) and 1.70 (1.66-1.74) ≥35 years (median), respectively. Immigrants born in Europe outside EU25, and countries outside Europe had particularly elevated HRs. Also in the second generation, HRs were higher in mental 1.29 (1.21-1.37) and somatic DP: 1.30 (1.19-1.42) in those <35 years; and 1.18 (1.10-1.27); and 1.10 (1.03-1.17) for those ≥35 years, respectively. Among second generation immigrants there were no strong differences in HRs between regions of birth. CONCLUSIONS: Compared to natives, the risk of DP was higher in first and second generation immigrants. Higher estimates were seen for immigrants from Europe outside EU25 and from the rest of the world in the first generation. No considerable differences in estimates regarding mental or somatic DP diagnoses were found.

Hospital-treated mental and behavioral disorders and risk of Alzheimer's disease: A nationwide nested case-control study.

BACKGROUND: Studies investigating psychiatric disorders as Alzheimer's disease (AD) risk factors have yielded heterogeneous findings. Differences in time windows between the exposure and outcome could be one explanation. We examined whether (1) mental and behavioral disorders in general or (2) specific mental and behavioral disorder categories increase the risk of AD and (3) how the width of the time window between the exposure and outcome affects the results. METHODS: A nationwide nested case-control study of all Finnish clinically verified AD cases, alive in 2005 and their age, sex and region of residence matched controls (n of case-control pairs 27,948). History of hospital-treated mental and behavioral disorders was available since 1972. RESULTS: Altogether 6.9% (n=1932) of the AD cases and 6.4% (n=1784) of controls had a history of any mental and behavioral disorder. Having any mental and behavioral disorder (adjusted OR=1.07, 95% CI=1.00-1.16) or depression/other mood disorder (adjusted OR=1.17, 95% CI=1.05-1.30) were associated with higher risk of AD with 5-year time window but not with 10-year time window (adjusted OR, 95% CI 0.99, 0.91-1.08 for any disorder and 1.08, 0.96-1.23 for depression). CONCLUSIONS: The associations between mental and behavioral disorders and AD were modest and dependent on the time window. Therefore, some of the disorders may represent misdiagnosed prodromal symptoms of AD, which underlines the importance of proper differential diagnostics among older persons. These findings also highlight the importance of appropriate time window in psychiatric and neuroepidemiology research.

Differences in analgesic use in community-dwelling persons with and without Alzheimer's disease.

BACKGROUND: There are conflicting findings about analgesic use among persons with cognitive impairment compared to cognitively intact older persons. The objective of our study was to investigate the prevalence of analgesic use in community-dwelling persons with and without Alzheimer's disease (AD), within six months after AD diagnosis and to find out factors associated with the use of analgesics and specific analgesic groups. METHOD: We utilized data from register based MEDALZ (Medication use and Alzheimer's disease) cohort consisting of all community-dwelling persons diagnosed with AD during 2005-2011 in Finland and their matched comparison persons without AD. Altogether, 67,215 persons with AD and one comparison person for each case were included. Drug use data were collected from the Prescription Register and comorbidities from Special Reimbursement and Hospital Discharge Registers. RESULTS: Statistically significant (p < 0.001) yet mostly small differences were found for analgesics use: analgesics were used by 34.9% and 33.5% of persons with and without AD, respectively. Paracetamol was the most frequently used analgesic both among persons with (25.0%) and without AD (19.1%). Persons with AD used less frequently NSAIDs (Nonsteroidal Anti-inflammatory Drugs) (13.2% vs. 17.3%) and mild opioids (5.0% vs. 7.1%), while the use of strong opioids was more common in comparison to persons without AD (1.3% vs. 1.1%, respectively). Analgesic users were more likely women, aged ≥80 years, had asthma/COPD, cardiovascular disease, diabetes, cancer, hip fracture, osteoporosis, rheumatoid arthritis, and lower socioeconomic position. CONCLUSION: Further studies are needed to evaluate the adequateness of pain relief in older persons with and without AD. SIGNIFICANCE: Persons with Alzheimer's disease (AD) used more frequently paracetamol and less frequently NSAIDs and mild opioids. A decreasing trend of NSAID use was observed among persons with AD during the study period.

Genome-wide association study of antisocial personality disorder.

The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N=370, N=5850 for controls, GWAS; N=173, N=3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR)=2.19 (1.53-3.14), P=1.9 × 10(-5)). Two polymorphisms at 6p21.2 LINC00951-LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR=1.59 (1.37-1.85), P=1.6 × 10(-9)) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (ß=0.68, P=0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder.

Influence of a HTR2B Stop Codon on Glucagon Homeostasis and Glucose Excursion in Non-Diabetic Men.

Limited data are available about the role of the serotonin 2B (5-HT2B) receptor in the function of human islets. This study aimed to test whether the 5-HT2B receptor contributes to glucose, insulin, and glucagon homeostasis in humans, utilizing a hereditary loss-of-function gene mutation in the receptor, which causes a 50% reduction in the production of the receptor protein in heterozygotes. This clinical study enrolled participants recruited by newspaper advertisements and from mental status examinations. A cohort of participants from a young Finnish founder population composed of 68 non-diabetic males with a mean age of 30 was divided into groups for comparison based on being a 5-HT2B receptor loss-of-function gene mutation (HTR2B Q20*) heterozygote carrier (n=11) or not (n=57). Serum levels of glucose, insulin, and glucagon were measured in a 5 h oral glucose tolerance test using a 75 g glucose challenge. Insulin resistance, insulin sensitivity, and beta cell activity were calculated using the homeostasis model assessment (HOMA2) and whole body insulin sensitivity index (WBISI), as well as the ratio of glucagon to insulin was noted. The areas under the curves (AUCs) were also determined. Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in cerebrospinal fluid (CSF). Covariate adjusted mean score comparisons were applied. Lower glucagon secretion and decreased glucose excursion were observed among HTR2B Q20* carriers as compared with individuals who were homozygotes for the wild-type Q20 allele (controls). No differences in insulin secretion, beta cell activity, insulin resistance, or insulin sensitivity were observed. The glucagon to insulin ratio differed between the HTR2B Q20* carriers and controls. CSF levels of 5-HIAA were similar between groups. Our findings indicate that the 5-HT2B receptor may contribute to the regulation of human glucagon and glucose homeostasis and the interplay between glucagon and insulin secretion.