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- Solmi, M, et al.
(author)
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- 2022
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In: Journal of affective disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 299, s. 367-376
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Journal article (peer-reviewed)
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| 2. |
- Tielbeek, J. J., et al.
(author)
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Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior
- 2017
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In: Jama Psychiatry. - : American Medical Association (AMA). - 2168-622X .- 2168-6238. ; 74:12, s. 1242-1250
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Journal article (peer-reviewed)abstract
- IMPORTANCE Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. OBJECTIVES To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). MAIN OUTCOME AND MEASURES This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. RESULTS The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R-2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P =.005) was detected. CONCLUSIONS AND RELEVANCE The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.
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| 3. |
- Hakkinen, K, et al.
(author)
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Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder
- 2022
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In: The pharmacogenomics journal. - : Springer Science and Business Media LLC. - 1473-1150 .- 1470-269X. ; 22:3, s. 166-172
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Journal article (peer-reviewed)abstract
- We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.
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- Tiihonen, J, et al.
(author)
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Sex-specific transcriptional and proteomic signatures in schizophrenia
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3933-
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Journal article (peer-reviewed)abstract
- It has remained unclear why schizophrenia typically manifests after adolescence and which neurobiological mechanisms are underlying the cascade leading to the actual onset of the illness. Here we show that the use of induced pluripotent stem cell-derived neurons of monozygotic twins from pairs discordant for schizophrenia enhances disease-specific signal by minimizing genetic heterogeneity. In proteomic and pathway analyses, clinical illness is associated especially with altered glycosaminoglycan, GABAergic synapse, sialylation, and purine metabolism pathways. Although only 12% of all 19,462 genes are expressed differentially between healthy males and females, up to 61% of the illness-related genes are sex specific. These results on sex-specific genes are replicated in another dataset. This implies that the pathophysiology differs between males and females, and may explain why symptoms appear after adolescence when the expression of many sex-specific genes change, and suggests the need for sex-specific treatments.
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- Toimela, J.S., et al.
(author)
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Association of obesity to reaction time and visual memory in schizophrenia
- 2024
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In: Schizophrenia Research. - : Elsevier. - 2215-0013. ; 37
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Journal article (peer-reviewed)abstract
- 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.
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| 24. |
- Basnet, S, et al.
(author)
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Characteristics of drug-abusing females with and without children seeking treatment in Helsinki, Finland
- 2015
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In: Scandinavian journal of public health. - : SAGE Publications. - 1651-1905 .- 1403-4948. ; 43:3, s. 221-228
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Journal article (peer-reviewed)abstract
- Aims: This study characterizes treatment-seeking female users of illicit drugs in Finland, and examines possible differences among women with or without children under 18. Methods: The subjects were 2526 drug-using clients from the Helsinki metropolitan area, who sought treatment at Helsinki Deaconess Institute between 2001 and 2008. A total of 775 (30.6%) were females with complete information regarding their parental status. Of these, 225 (29%) had children under 18. The proportion of women with children varied between 20% and 30% annually, except in 2006, when it peaked at 40.5%. Results: Women with children were more likely to be somewhat older ( p<0.001), married or cohabiting ( p<0.001), homeless ( p=0.007), unemployed ( p<0.001), and living with other illicit drug users ( p=0.014), compared with those without children. Self-referral and referral to treatment by child healthcare services were more common among those who had children ( p<0.001). A higher proportion of women with children reported use of opiates as the primary drug ( p<0.001), and used them more often intravenously ( p=0.001), and daily ( p=0.007), during the previous month. However, polydrug use ( p=0.607) and sharing of needles/syringes ( p=0.945) were similar in both groups. Prevalence of hepatitis B and C ( p=0.041 and p<0.001, respectively) were more common in females with children. Among women who had children, 34.2% had children living within the same household, 37.3% in foster care, and 22.7% elsewhere. Conclusions: Women with children had more risky drug consumption patterns, and were more likely to live with other drug users; this creates an unhealthy environment for child rearing.
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- Konte, B, et al.
(author)
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HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry
- 2021
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In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1, s. 214-
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Journal article (peer-reviewed)abstract
- The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E−06) and agranulocytosis (OR = 10.49, P = 1.83E−06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E−08; agranulocytosis: OR = 16.31, P = 1.39E−06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.
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| 37. |
- Okhuijsen-Pfeifer, C, et al.
(author)
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Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders
- 2022
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In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 12:1, s. 145-
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Journal article (peer-reviewed)abstract
- 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.
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| 48. |
- Taipale, H, et al.
(author)
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Health and work disability outcomes in parents of patients with schizophrenia associated with antipsychotic exposure by the offspring
- 2020
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 1219-
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Journal article (peer-reviewed)abstract
- This study aimed to identify if antipsychotic exposure in offspring is associated with psychiatric and non-psychiatric healthcare service use and work disability of their parents. This Swedish population-based cohort study was based on data comprising 10,883 individuals with schizophrenia, who had at least one identifiable parent in the nationwide registers, and their parents (N = 18,215). The register-based follow-up during 2006–2013 considered the level of antipsychotic exposure and persistence of use of the offspring, further categorized into first (FG) and second generation (SG) antipsychotics, and orals versus long-acting injections (LAIs). The main outcome measure was parental psychiatric healthcare service use, secondary outcomes were non-psychiatric healthcare use and long-term sickness absence. SG-LAI use was associated with a decreased risk (relative risks [RR] 0.81-0.85) of parental psychiatric healthcare use compared with not using SG-LAI, whereas oral antipsychotics were associated with an increased risk (RRs 1.10–1.29). Both FG- and SG-LAI use by the offspring were associated with a lower risk of long-term sickness absence (range of odds ratios 0.34–0.47) for the parents, compared with non-use of these drugs. The choice of antipsychotic treatment for the offspring may have an impact on work disability and healthcare service use of their parents.
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