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  • O'Dushlaine, C, et al. (författare)
  • Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways
  • 2015
  • Ingår i: Nature neuroscience. - 1546-1726. ; 18:2, s. 199-209
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
  • Lee, S. Hong, et al. (författare)
  • Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs
  • 2013
  • Ingår i: Nature genetics. - 1546-1718. ; 45:9, s. 984-
  • Tidskriftsartikel (refereegranskat)abstract
    • Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders. © 2013 Nature America, Inc. All rights reserved.
  • Reinbold, C. S., et al. (författare)
  • Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder
  • 2018
  • Ingår i: Frontiers in Psychiatry. - 1664-0640. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen) Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD associated miRNAs However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.
  • Stahl, Eli A, et al. (författare)
  • Genome-wide association study identifies 30 loci associated with bipolar disorder
  • 2019
  • Ingår i: Nature Genetics. - 1061-4036. ; 51:5, s. 793-803
  • Tidskriftsartikel (refereegranskat)abstract
    • Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
  • Lavebratt, C., et al. (författare)
  • The KMO allele encoding Arg(452) is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression
  • 2014
  • Ingår i: Molecular Psychiatry. - Nature Publishing Group. - 1359-4184. ; 19:3, s. 334-341
  • Tidskriftsartikel (refereegranskat)abstract
    • The kynurenine pathway metabolite kynurenic acid (KYNA), modulating glutamatergic and cholinergic neurotransmission, is increased in cerebrospinal fluid (CSF) of patients with schizophrenia or bipolar disorder type 1 with psychotic features. KYNA production is critically dependent on kynurenine 3-monooxygenase (KMO). KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. We hypothesized that KMO expression in PFC would be reduced in bipolar disorder with psychotic features and that a functional genetic variant of KMO would associate with this disease, CSF KYNA level and KMO expression. KMO mRNA levels were reduced in PFC of bipolar disorder patients with lifetime psychotic features (P = 0.005, n = 19) or schizophrenia (P = 0.02, n = 36) compared with nonpsychotic patients and controls. KMO genetic association to psychotic features in bipolar disorder type 1 was studied in 493 patients and 1044 controls from Sweden. The KMO Arg(452) allele was associated with psychotic features during manic episodes (P = 0.003). KMO Arg(452) was studied for association to CSF KYNA levels in an independent sample of 55 Swedish patients, and to KMO expression in 717 lymphoblastoid cell lines and 138 hippocampal biopsies. KMO Arg(452) associated with increased levels of CSF KYNA (P = 0.03) and reduced lymphoblastoid and hippocampal KMO expression (P <= 0.05). Thus, findings from five independent cohorts suggest that genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes.
  • Musliner, Katherine L., et al. (författare)
  • Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia With Risk for Depression in the Danish Population
  • 2019
  • Ingår i: JAMA psychiatry. - Chicago : American Medical Association. - 2168-6238. ; 76:5, s. 516-525
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored.OBJECTIVE: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis.DESIGN SETTING AND PARTICIPANTS: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018.EXPOSURES: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium.MAIN OUTCOMES AND MEASURES: The main outcome was first depressive episode (international Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency).RESULTS: Of 34 573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (beta =-.07; SE =.02; P =.002).CONCLUSIONS AND RELEVANCE: Polygenic ability for MD is associated with first depress on in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.
  • Örtqvist, L, et al. (författare)
  • Psychiatric symptoms in men with hypospadias - preliminary results of a cross-sectional cohort study
  • 2019
  • Ingår i: Acta Paediatrica. - 0803-5253. ; 108:6, s. 1156-1162
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim Population studies have shown an increased risk of neurodevelopmental disorders in males born with the congenital condition hypospadias, where the opening of the urethra is on the underside of the penis. We investigated overall psychiatric morbidity in cases and matched controls. Methods This study compared 167 men born with hypospadias from 1959 to 1994 in Stockholm or Gothenburg in Sweden using hospital registers. They were compared with controls from the Swedish population registry, who were contacted by regular mail and students who were recruited by local advertisements. The total sample had a mean age of 33.5 years (range: 19-54). They completed self-rating scales for depressive, anxiety and obsessive-compulsive symptoms and symptoms of attention deficit hyperactivity disorder. In addition, 33 cases and 47 controls underwent psychiatric morbidity interviews that covered the 17 most common psychiatric diagnoses. Results A fifth (21%) of both the cases and controls reported current or previous psychiatric symptoms. There were no significant differences in self-rated depression, anxiety or obsessive-compulsive disorder symptoms between the patients and controls or between the different phenotype groups. The distribution was not significantly affected by the severity of hypospadias. Conclusion Psychiatric morbidity was no higher in men with hypospadias than population-based controls.
  • Örtqvist, L, et al. (författare)
  • Psychosocial outcome in adult men born with hypospadias
  • 2017
  • Ingår i: Journal of Pediatric Urology. - 1477-5131 .- 1873-4898. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Hypospadias, which is a surgically treated congenital malformation of the male urethra, may have a negative impact on quality of life. This aspect has previously been subject to limited research. This study examined the long-term psychosocial outcome of a large cohort of adult males born with hypospadias. Objective The purpose of this case–control study was to assess a possible negative influence on the psychosocial outcome in adult males with hypospadias. Study design Males with hypospadias treated in Sweden and aged ≥18 years old participated in this follow-up study. Age-matched men and university students were recruited as controls. The participants answered a questionnaire designed to reflect the subjective quality of life, social factors, need of support and follow-up, and the perceived impact of the disease upon upbringing. It also looked at the validated Psychological General Well-Being (PGWB) questionnaire and Relationship Questionnaire (RQ). Results and discussion A total of 167 patients (median age 34 years, 63% distal, 24% mid, and 13% proximal hypospadias) and 169 controls (median age 33 years) participated in the study. Patients had their first operation at 4 years of age (median) and the median follow-up time was 29 years following the first surgery. Men with hypospadias had a comparable total quality of life level with a mean total PGWB score of 82 (normal range 78–83) compared with 85.6 in controls. Scores on wellbeing and vitality were lower, even if the differences were small. Hypospadias did not affect marital status, presence of children in the family, frequency of employment or experience of bullying. These men more often lived at home with their parents (P=0.001) and had a lower level of education (P=0.004), even if the educational level in both patients and controls was high compared with the general Swedish population. Patients with proximal hypospadias were shorter compared with controls (P=0.003), which was consistent with the prenatal growth restriction associated with hypospadias. The group with proximal hypospadias expressed a greater need for medical (45.5%) follow-up compared with mid (28.2%) and distal (18.1%) cases (P=0.001). Patients with proximal hypospadias tended to avoid close relationships because of fear of being hurt. Conclusions The findings suggested that patients treated for hypospadias have a good HRQoL, can be expected to have a normal psychosocial life, and marry and have children. Repeated follow-up and psychological support during childhood/adolescence is however of great importance for patients with more proximal hypospadias.
  • Örtqvist, L, et al. (författare)
  • Sexuality and fertility in men with hypospadias; improved outcome.
  • 2017
  • Ingår i: Andrology. - 2047-2927. ; 5:2, s. 286-293
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to investigate sexual function and fertility in adult men born with hypospadias. Patients born with hypospadias, age-matched controls, and a group of circumcised men completed a questionnaire constructed to reflect their psychosexual situation and fertility. Core gender identity, sexual orientation, and gender role behavior was also assessed. 167 patients [63% distal, 24% mid shaft and 13% proximal, mean age 34 (19-54) years], 169 controls from the general population [mean age 33 (19-48) years] and 47 controls circumcised because of phimosis (mean age 26 [19-44]) participated and completed the questionnaire. There were no differences in having a partner, reported fertility, age at sexarche (mean age 17.8), number of sex partners or sexual interest between the patients and controls. More patients than controls reported anejaculation. Reported glanular sensitivity was lower in hypospadias patients and circumcised controls compared with non-circumcised controls. The odds of being satisfied with their sexual life increased with a higher penile perception score in patients (OR = 1.54, p = 0.01). There was no association with penile length. Sexual orientation, core gender identity and gender role behavior were sex-typical in both patients and controls. Patients with proximal hypospadias had a lower reported fertility, experienced anejaculation more often, and were less satisfied with their sexual life. Men born with hypospadias have a good long-term outcome concerning sexual function and fertility. Men born with proximal hypospadias have a more impaired outcome concerning both sexual function and fertility. As satisfaction with genital appearance is important for sexual life satisfaction, clinical, and psychological follow-up into adulthood is especially important in boys born with proximal hypospadias.
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