Associations between genetic liabilities to smoking behavior and schizophrenia symptoms in patients with a psychotic disorder, their siblings and healthy controls

It is unknown how smoking behavior polygenic scores (PRS) relate to psychosis and psychotic symptoms. To elucidate this, genotype and phenotype data were collected from patients with schizophrenia, their unaffected siblings, and healthy controls in a six-year follow-up prospective cohort study. Associations between smoking behaviors, PRS and schizophrenia symptoms were explored using linear mixed-effect models. The mean number of cigarettes smoked per day were 18 for patients, 13 for siblings and 12 for controls. In the overall sample, PRSs-smoking initiation (i.e., ever smoking as a binary phenotype, PRS-SI) were positively associated with positive symptoms, negative symptoms, and depressive symptoms, whereas PRSs-AI (age at regular smoking initiation) were negatively associated with all symptom dimensions, with similar effect sizes. When considering groups separately, PRS were only associated with psychotic symptoms in siblings and controls. In conclusion, unaffected siblings show smoking behaviors at an intermediate level between patients and healthy controls. Additionally, PRS-SI and PRS-AI are associated with all symptom dimensions only in unaffected siblings and healthy controls, possibly owing to the dominant role of other (genetic) risk factors in patients. Future studies may examine mechanisms via which genetic risk for smoking affects mental health symptoms.</p

The distinct traits of the UNC13A polymorphism in amyotrophic lateral sclerosis

OBJECTIVE: The rs12608932 single nucleotide polymorphism in UNC13A is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype of UNC13A in patients with ALS. METHODS: We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. A subcohort of 428 patients with ALS was used to study cognitive and behavioral profiles, and 375 patients to study neuroimaging characteristics. Associations were analyzed under an additive genetic model. RESULTS: Genotyping rs12608932 resulted in 854 A/A, 988 A/C, and 374 C/C genotypes. The C allele was associated with a higher age at symptom onset (median years A/A 63.5, A/C 65.6, and C/C 65.5; p < 0.001), more frequent bulbar onset (A/A 29.6%, A/C 31.8%, and C/C 43.1%; p < 0.001), higher incidences of ALS-FTD (A/A 4.3%, A/C 5.2%, and C/C 9.5%; p = 0.003), lower forced vital capacity at diagnosis (median percentage A/A 92.0, A/C 90.0, and C/C 86.5; p < 0.001), and a shorter survival (median in months A/A 33.3, A.C 30.7, and C/C 26.6; p < 0.001). UNC13A was associated with lower scores on ALS-specific cognition tests (means A/A 79.5, A/C 78.1, and C/C 76.6; p = 0.037), and more frequent behavioral disturbances (A/A 16.7%, A/C 24.4%, and C/C 27.7%; p = 0.045). Thinner left inferior temporal and right fusiform cortex were associated with the UNC13A single nucleotide polymorphism (SNP; p = 0.045 and p = 0.036). INTERPRETATION: Phenotypical distinctions associated with UNC13A make it an important factor to take into account in clinical trial design, studies on cognition and behavior, and prognostic counseling. ANN NEUROL 2020;88:796-806

Phenome-wide and genome-wide analyses of quality of life in schizophrenia

This article has been published in a revised form in BJPsych Open [http://doi.org/10.1192/bjo.2020.140]. This version is free to view and download for private research and study only. Not for re-distribution or re-use. © copyright holder.Background Schizophrenia negatively affects quality of life (QoL). A handful of variables from small studies have been reported to influence QoL in patients with schizophrenia, but a study comprehensively dissecting the genetic and non-genetic contributing factors to QoL in these patients is currently lacking. Aims We adopted a hypothesis-generating approach to assess the phenotypic and genotypic determinants of QoL in schizophrenia. Method The study population comprised 1119 patients with a psychotic disorder, 1979 relatives and 586 healthy controls. Using linear regression, we tested >100 independent demographic, cognitive and clinical phenotypes for their association with QoL in patients. We then performed genome-wide association analyses of QoL and examined the association between polygenic risk scores for schizophrenia, major depressive disorder and subjective well-being and QoL. Results We found nine phenotypes to be significantly and independently associated with QoL in patients, the most significant ones being negative (β = −1.17; s.e. 0.05; P = 1 × 10–83; r2 = 38%), depressive (β = −1.07; s.e. 0.05; P = 2 × 10–79; r2 = 36%) and emotional distress (β = −0.09; s.e. 0.01; P = 4 × 10–59, r2 = 25%) symptoms. Schizophrenia and subjective well-being polygenic risk scores, using various P-value thresholds, were significantly and consistently associated with QoL (lowest association P-value = 6.8 × 10–6). Several sensitivity analyses confirmed the results. Conclusions Various clinical phenotypes of schizophrenia, as well as schizophrenia and subjective well-being polygenic risk scores, are associated with QoL in patients with schizophrenia and their relatives. These may be targeted by clinicians to more easily identify vulnerable patients with schizophrenia for further social and clinical interventions to improve their QoL.Dutch Health Research Council; Lundbeck; AstraZeneca; Eli Lilly; Janssen Cilag;Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions at Geestelijke Gezondheidszorg (GGZ) Ingeest; Arkin; Dijk en Duin; GGZ Rivierduinen; Erasmus Medical Centre and GGZ Noord Holland Noord; Groningen: University Medical Center Groningen and the mental health institutions at Lentis; GGZ Friesland; GGZ Drenthe; Dimence; Mediant; GGNet Warnsveld; Yulius Dordrecht and Parnassia Psycho-Medical Center The Hague; Maastricht: Maastricht University Medical Centre and the mental health institutions at GGZ Eindhoven en De Kempen; GGZ Breburg; GGZ Oost-Brabant; Vincent van Gogh voor Geestelijke Gezondheid; Mondriaan; Virenze riagg; Zuyderland GGZ; MET ggz; Universitair Centrum Sint-Jozef Kortenberg; Collaborative Antwerp Psychiatric Research Institute University of Antwerp; Psychiatrisch Centrum Ziekeren Sint-Truiden; Psychiatrisch Ziekenhuis Sancta Maria Sint-Truiden; GGZ Overpelt and Openbaar Psychiatrisch Zorgcentrum Rekem; Utrecht: University Medical Center Utrecht and the mental health institutions Altrecht; GGZ Centraal and Delt

Childhood maltreatment mediates the effect of the genetic background on psychosis risk in young adults

Childhood maltreatment (CM) and genetic vulnerability are both risk factors for psychosis, but the relations between them are not fully understood. Guided by the recent identification of genetic risk to CM, this study investigates the hypothesis that genetic risk to schizophrenia also increases the risk of CM and thus impacts psychosis risk. The relationship between schizophrenia polygenetic risk, CM, and psychotic-like experiences (PLE) was investigated in participants from the Utrecht Cannabis Cohort (N = 1262) and replicated in the independent IMAGEN cohort (N = 1740). Schizophrenia polygenic risk score (SZ-PRS) were calculated from the most recent GWAS. The relationship between CM, PRS, and PLE was first investigated using multivariate linear regression. Next, mediation of CM in the pathway linking SZ-PRS and PLE was examined by structural equation modeling, while adjusting for a set of potential mediators including cannabis use, smoking, and neuroticism. In agreement with previous studies, PLE were strongly associated with SZ-PRS (B = 0.190, p = 0.009) and CM (B = 0.575, p &lt; 0.001). Novel was that CM was also significantly associated with SZ-PRS (B = 0.171, p = 0.001), and substantially mediated the effects of SZ-PRS on PLE (proportion mediated = 29.9%, p = 0.001). In the replication cohort, the analyses yielded similar results, confirming equally strong mediation by CM (proportion mediated = 34.7%, p = 0.009). Our results suggest that CM acts as a mediator in the causal pathway linking SZ-PRS and psychosis risk. These findings open new perspectives on the relations between genetic and environmental risks and warrant further studies into potential interventions to reduce psychosis risk in vulnerable people

Analysis of FUS, PFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy

Objective To investigate mutations in genes that are potential modifiers of spinal muscular atrophy (SMA) severity. Methods We performed a hypothesis-based search into the presence of variants in fused in sarcoma (FUS), transactive response DNA-binding protein 43 (TDP-43), plastin 3 (PLS3), and profilin 2 (PFN2) in a cohort of 153 patients with SMA types 1-4, including 19 families. Variants were detected with targeted next-generation sequencing and confirmed with Sanger sequencing. Functional effects of the identified variants were analyzed in silico and for PLS3, by analyzing expression levels in peripheral blood. Results We identified 2 exonic variants in FUS exons 5 and 6 (p.R216C and p.S135N) in 2 unrelated patients, but clinical effects were not evident. We identified 8 intronic variants in PLS3 in 33 patients. Five PLS3 variants (c.1511+82T>C; c.748+130 G>A; c.367+182C>T; c.891-25T>C (rs145269469); c.1355+17A>G (rs150802596)) potentially alter exonic splice silencer or exonic splice enhancer sites. The variant c.367+182C>T, but not RNA expression levels, corresponded with a more severe phenotype in 1 family. However, this variant or level of PLS3 expression did not consistently correspond with a milder or more severe phenotype in other families or the overall cohort. We found 3 heterozygous, intronic variants in PFN2 and TDP-43 with no correlation with clinical phenotype or effects on splicing. Conclusions PLS3 and FUS sequence variants do not modify SMA severity at the population level. Specific variants in individual patients or families do not consistently correlate with disease severity

Childhood maltreatment mediates the effect of the genetic background on psychosis risk in young adults

Childhood maltreatment (CM) and genetic vulnerability are both risk factors for psychosis, but the relations between them are not fully understood. Guided by the recent identification of genetic risk to CM, this study investigates the hypothesis that genetic risk to schizophrenia also increases the risk of CM and thus impacts psychosis risk. The relationship between schizophrenia polygenetic risk, CM, and psychotic-like experiences (PLE) was investigated in participants from the Utrecht Cannabis Cohort (N = 1262) and replicated in the independent IMAGEN cohort (N = 1740). Schizophrenia polygenic risk score (SZ-PRS) were calculated from the most recent GWAS. The relationship between CM, PRS, and PLE was first investigated using multivariate linear regression. Next, mediation of CM in the pathway linking SZ-PRS and PLE was examined by structural equation modeling, while adjusting for a set of potential mediators including cannabis use, smoking, and neuroticism. In agreement with previous studies, PLE were strongly associated with SZ-PRS (B = 0.190, p = 0.009) and CM (B = 0.575, p

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC?2 pathway as drug-target

Association of Risk Variants in the <i>CFH </i>Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis

Importance: Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. Objective: To identify the genes and pathways associated with idiopathic MFC. Design, Setting, and Participants: This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Main outcomes and measures: Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. Results: This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10-8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Conclusions and relevance: Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.</p

Age- and sex-specific associations between risk scores for schizophrenia and self-reported health in the general population

Purpose The health correlates of polygenic risk (PRS-SCZ) and exposome (ES-SCZ) scores for schizophrenia may vary depending on age and sex. We aimed to examine age- and sex-specific associations of PRS-SCZ and ES-SCZ with self-reported health in the general population. Methods Participants were from the population-based Netherlands Mental Health Survey and Incidence Study–2 (NEMESIS-2). Mental and physical health were measured with the 36-item Short Form Survey 4 times between 2007 and 2018. The PRS-SCZ and ES-SCZ were respectively calculated from common genetic variants and exposures (cannabis use, winter birth, hearing impairment, and five childhood adversity categories). Moderation by age and sex was examined in linear mixed models. Results For PRS-SCZ and ES-SCZ analyses, we included 3099 and 6264 participants, respectively (age range 18–65 years; 55.7–56.1% female). Age and sex did not interact with PRS-SCZ. Age moderated the association between ES-SCZ and mental (interaction: p = 0.02) and physical health (p = 0.0007): at age 18, + 1.00 of ES-SCZ was associated with − 0.10 of mental health and − 0.08 of physical health, whereas at age 65, it was associated with − 0.21 and − 0.23, respectively (all units in standard deviations). Sex moderated the association between ES-SCZ and physical health (p < .0001): + 1.00 of ES-SCZ was associated with − 0.19 of physical health among female and − 0.11 among male individuals. Conclusion There were larger associations between higher ES-SCZ and poorer health among female and older individuals. Accounting for these interactions may increase ES-SCZ precision and help uncover populational determinants of environmental influences on health

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer’s disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.Fil:  van der Lee, Sven J.. Vrije Universiteit Amsterdam; Países BajosFil: Conway, Olivia J.. Mayo Clinic Cancer Center; Estados UnidosFil: Jansen, Iris. Vrije Universiteit Amsterdam; Países BajosFil: Carrasquillo, Minerva M.. Mayo Clinic Cancer Center; Estados UnidosFil: Kleineidam, Luca. Universitat Bonn; Alemania. German Center for Neurodegenerative Diseases; Alemania. University Hospital Cologne; AlemaniaFil: van den Akker, Erik. Leiden University. Leiden University Medical Center; Países Bajos. Delft University of Technology; Países BajosFil: Hernández, Isabel. Universitat Internacional de Catalunya; España. Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas ; EspañaFil: van Eijk, Kristel R.. University of Utrecht; Países BajosFil: Stringa, Najada. Vrije Universiteit Amsterdam; Países BajosFil: Chen, Jason A.. University of California at Los Angeles; Estados UnidosFil: Zettergren, Anna. University of Gothenburg; SueciaFil: Andlauer, Till F. M.. Max Planck Institute of Psychiatry; Alemania. Universitat Technical Zu Munich; Alemania. German Competence Network Multiple Sclerosis; AlemaniaFil: Diez Fairen, Monica. University Hospital Mutua de Terrassa; España. Fundacio per la Recerca Biomedica I Social Mutua Terrassa; EspañaFil: Simon Sanchez, Javier. Deutsches Zentrum für Neurodegenerative Erkrankungen; Alemania. Eberhard Karls Universität Tübingen; AlemaniaFil: Lleó, Alberto. Universitat Autònoma de Barcelona; España. Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas ; EspañaFil: Zetterberg, Henrik. Sahlgrenska University Hospital; Suecia. University of Gothenburg; Suecia. University College London; Estados UnidosFil: Nygaard, Marianne. University of Southern Denmark; DinamarcaFil: Blauwendraat, Cornelis. National Institute of Neurological Disorders and Stroke; Estados UnidosFil: Savage, Jeanne E.. Vrije Universiteit Amsterdam; Países BajosFil: Mengel From, Jonas. University of Southern Denmark; DinamarcaFil: Moreno Grau, Sonia. Universitat Internacional de Catalunya; EspañaFil: Wagner, Michael. Universitat Bonn; Alemania. Deutsches Zentrum für Neurodegenerative Erkrankungen; AlemaniaFil: Fortea, Juan. Universitat Autònoma de Barcelona; España. Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas ; EspañaFil: Keogh, Michael J.. University of Newcastle; Reino Unido. University of Cambridge; Reino UnidoFil: Blennow, Kaj. Sahlgrenska University Hospital; Suecia. University of Gothenburg; SueciaFil: Skoog, Ingmar. University of Gothenburg; SueciaFil: Friese, Manuel A.. German Competence Network Multiple Sclerosis; Alemania. Universitätsklinikum Hamburg‐Eppendorf; AlemaniaFil: Pletnikova, Olga. University Johns Hopkins; Estados UnidosFil: Zulaica, Miren. Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas ; España. Instituto Biodonostia; EspañaFil: Dalmasso, Maria Carolina. University Hospital Cologne; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin