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Background There is evidence for a polygenic contribution to psychosis. One targetable mechanism through which polygenic variation may impact on individuals and interact with the social environment is stress sensitization, characterized by elevated reactivity to minor stressors in daily life. The current study aimed to investigate whether stress reactivity is modified by polygenic risk score for schizophrenia (PRS) in cases with enduring non-affective psychotic disorder, first-degree relatives of cases, and controls. Methods We used the experience sampling method to assess minor stressors, negative affect, positive affect and psychotic experiences in 96 cases, 79 first-degree relatives, i.e. siblings, and 73 controls at wave 3 of the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. Genome-wide data were collected at baseline to calculate PRS. Results We found that associations of momentary stress with psychotic experiences, but not with negative and positive affect, were modified by PRS and group (all pFWEv. low level of PRS. By contrast, controls with high PRS showed more intense psychotic experiences in response to stress compared to those with low PRS. Conclusions This tentatively suggests that polygenic risk may operate in different ways than previously assumed and amplify reactivity to stress in unaffected individuals but operate as a resilience factor in relatives by attenuating their stress reactivity.

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 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.

Little is known about the genetic determinants of medication use in preventing cardiometabolic diseases. Using the Finnish nationwide drug purchase registry with follow-up since 1995, we performed genome-wide association analyses of longitudinal patterns of medication use in hyperlipidemia, hypertension and type 2 diabetes in up to 193,933 individuals (55% women) in the FinnGen study. In meta-analyses of up to 567,671 individuals combining FinnGen with the Estonian Biobank and the UK Biobank, we discovered 333 independent loci (P –9) associated with medication use. Fine-mapping revealed 494 95% credible sets associated with the total number of medication purchases, changes in medication combinations or treatment discontinuation, including 46 credible sets in 40 loci not associated with the underlying treatment targets. The polygenic risk scores (PRS) for cardiometabolic risk factors were strongly associated with the medication-use behavior. A medication-use enhanced multitrait PRS for coronary artery disease matched the performance of a risk factor-based multitrait coronary artery disease PRS in an independent sample (UK Biobank, n = 343,676). In summary, we demonstrate medication-based strategies for identifying cardiometabolic risk loci and provide genome-wide tools for preventing cardiovascular diseases.

La schizofrenia e altri disturbi psicotici sono disturbi complessi con eziologia multifattoriale che comprende fattori genetici e ambientali. L’architettura genetica di questi disturbi coinvolge numerosi loci implicati nel conferire il rischio di sviluppare la malattia. Inoltre, gli studi che indagano l’eziologia molecolare di questi disturbi hanno mostrato un interesse crescente per le variazioni epigenetiche, specialmente la metilazione del DNA. I disturbi della social cognition, come le difficoltà nel riconoscimento delle emozioni facciali (FER), sono associati con i disturbi psicotici; tuttavia, il loro legame con la genetica e l’epigenetica di questi disturbi sono questioni ancora aperte. I dati utilizzati in questa tesi provengono da due studi: lo studio multicentrico di incidenza e casocontrollo EU-GEI e lo studio di follow-up Sicilian Genetics and Psychosis (SGAP follow-up). Il riconoscimento globale e specifico delle emozioni facciali è stato analizzato attraverso modelli mixed effect tra casi e controlli. Sono stati utilizzati modelli di regressione lineare multipla per studiare l’associazione del FER con il punteggio di rischio poligenico per la schizofrenia (SZ PRS) e, per la prima volta, con i profili di metilazione differenziale del DNA dell’intero genoma (Differentially Methylated Positions – DMPs). In un sottocampione di controlli reclutati a Palermo è stato condotto un follow up a 8 anni ed è stata analizzata la correlazione tra FER a baseline e il cambiamento della sintomatologia subclinica (esperienze simil-psicotiche e schizotipia). I pazienti psicotici presentavano più frequentemente deficit nel riconoscimento delle emozioni facciali rispetto ai controlli, in particolare nel riconoscimento della paura e della rabbia rispetto ai volti felici o neutri. Lo SZ PRS è stato associato a un peggiore riconoscimento globale delle emozioni facciali e in particolare nel riconoscimento della rabbia. Sono state identificate diverse DMPs associate al FER che, sebbene non raggiungessero la soglia di significatività epigenome-wide, erano localizzate in geni espressi a livello del sistema nervoso centrale e già replicati in altri studi di associazione epigenome-wide (EWAS) nella schizofrenia. Infine, compromissioni del riconoscimento delle emozioni negative correlavano con cambiamenti nella schizotipia e nei sintomi subclinici dopo otto anni in un campione della popolazione generale di Palermo. 5 L’analisi EWAS rappresenta una prima indagine esplorativa sul riconoscimento delle emozioni facciali che suggerisce ulteriori sviluppi per la ricerca epigenetica su questo dominio. I risultati sul FER rappresentano ulteriori evidenze riguardo alla compromissione del riconoscimento globale e specifico delle emozioni facciali nel contesto della psicosi, corroborando i precedenti risultati degli studi su familiari e suggerendo come il riconoscimento delle emozioni facciali - in particolare le emozioni negative - possa essere un fenotipo intermedio per la psicosi.

Background Family history of affective disorders has long been recognized as one of the strongest risk factors for the onset and maintenance of the disorders. Familial risk for affective disorders represents an integration of an underlying genetic vulnerability and the familial clustering of unfavorable family circumstances in (early) life. In order to alleviate some of the burden that affective disorders are causing, it is necessary to better understand how the disorders and their associated features operate within families to increase psychopathology. This thesis extensively examined familial risk for affective disorders, with a broad focus on the role of genetic, clinical, and psychosocial vulnerability, and poor immunometabolic health. Methods Data came from the Netherlands Study of Depression and Anxiety (NESDA), an ongoing longitudinal cohort study (2004-present) on the long-term course and consequences of affective disorders. The baseline sample consisted of 2,981 participants (18-65 years), including 2,319 persons with a lifetime affective disorder and 652 healthy controls. Participants were assessed in face-to-face interviews at baseline and 2-, 4-, 6-, and 9-year follow-up. Among a broad range of demographic, psychiatric, genetic, and biopsychosocial measures, the 9-year follow-up included a detailed family history assessment; 1,425 lifetime affected NESDA participants had valid family history data. During the 9-year follow-up, full-biological siblings of NESDA participants with a lifetime affective disorder (i.e. ‘probands’) were additionally recruited to participate in the NESDA sibling study. This included a total of 380 siblings, related to 256 probands (N = 636 from 256 families). Discussion of main findings Lifetime affected patients with higher familial risk showed higher genetic vulnerability and a more unfavorable disease and psychosocial risk profile. Although a dichotomous family history measure is an informative indicator, familial risk for affective disorders seems to be better captured by a continuous score that incorporates family- and disorder-specific characteristics. Furthermore, prevalence of current (26.8%) and lifetime (50.3%) affective disorders in siblings of lifetime affected probands was substantial, and two- to three- times higher as compared to Dutch population frequencies. As compared to healthy controls without affected relatives, probands’ unaffected siblings showed enhanced social vulnerability and rumination. Despite this, the majority of affective symptoms and psychosocial vulnerabilities were, in fact, not elevated in unaffected siblings as compared to healthy controls, which may indicate their underlying resilience. Moreover, proband-sibling resemblance in affective symptoms, psychosocial vulnerability, and poor immunometabolic health was mild to moderate, indicating that these features, to a certain extent, cluster within families, but that lifetime affected patients and their siblings still show considerable individual differences despite their shared familial disposition. Finally, between siblings of the same at-risk family, cross-trait associations of affective symptoms appear to be relevant in the link with psychosocial vulnerability, but less in the link with poor immunometabolic health. Concluding remarks Findings illustrate that familial risk for affective disorders is a complex and dimensional construct that deserves attention in research and clinical practice. Having identified a wide variety of clinically-relevant factors that may explain heightened familial risk, the next generation of research should focus on preventing the onset of affective disorders and fostering resilience in at-risk relatives. Both within research and clinical practice, it is of particular importance to direct attention to family members when evaluating the risk for affective disorders, as this may contribute to a better understanding of the role of within-family processes in the etiology and maintenance of the disorders, and help identify pathways through which resilience is promoted. This knowledge may ultimately contribute to more effective treatment, the early identification of affective problems, and possibly preventing new onset of disorder, severe disability and intensive treatment in those at the highest risk.

Background Family history of affective disorders has long been recognized as one of the strongest risk factors for the onset and maintenance of the disorders. Familial risk for affective disorders represents an integration of an underlying genetic vulnerability and the familial clustering of unfavorable family circumstances in (early) life. In order to alleviate some of the burden that affective disorders are causing, it is necessary to better understand how the disorders and their associated features operate within families to increase psychopathology. This thesis extensively examined familial risk for affective disorders, with a broad focus on the role of genetic, clinical, and psychosocial vulnerability, and poor immunometabolic health. Methods Data came from the Netherlands Study of Depression and Anxiety (NESDA), an ongoing longitudinal cohort study (2004-present) on the long-term course and consequences of affective disorders. The baseline sample consisted of 2,981 participants (18-65 years), including 2,319 persons with a lifetime affective disorder and 652 healthy controls. Participants were assessed in face-to-face interviews at baseline and 2-, 4-, 6-, and 9-year follow-up. Among a broad range of demographic, psychiatric, genetic, and biopsychosocial measures, the 9-year follow-up included a detailed family history assessment; 1,425 lifetime affected NESDA participants had valid family history data. During the 9-year follow-up, full-biological siblings of NESDA participants with a lifetime affective disorder (i.e. ‘probands’) were additionally recruited to participate in the NESDA sibling study. This included a total of 380 siblings, related to 256 probands (N = 636 from 256 families). Discussion of main findings Lifetime affected patients with higher familial risk showed higher genetic vulnerability and a more unfavorable disease and psychosocial risk profile. Although a dichotomous family history measure is an informative indicator, familial risk for affective disorders seems to be better captured by a continuous score that incorporates family- and disorder-specific characteristics. Furthermore, prevalence of current (26.8%) and lifetime (50.3%) affective disorders in siblings of lifetime affected probands was substantial, and two- to three- times higher as compared to Dutch population frequencies. As compared to healthy controls without affected relatives, probands’ unaffected siblings showed enhanced social vulnerability and rumination. Despite this, the majority of affective symptoms and psychosocial vulnerabilities were, in fact, not elevated in unaffected siblings as compared to healthy controls, which may indicate their underlying resilience. Moreover, proband-sibling resemblance in affective symptoms, psychosocial vulnerability, and poor immunometabolic health was mild to moderate, indicating that these features, to a certain extent, cluster within families, but that lifetime affected patients and their siblings still show considerable individual differences despite their shared familial disposition. Finally, between siblings of the same at-risk family, cross-trait associations of affective symptoms appear to be relevant in the link with psychosocial vulnerability, but less in the link with poor immunometabolic health. Concluding remarks Findings illustrate that familial risk for affective disorders is a complex and dimensional construct that deserves attention in research and clinical practice. Having identified a wide variety of clinically-relevant factors that may explain heightened familial risk, the next generation of research should focus on preventing the onset of affective disorders and fostering resilience in at-risk relatives. Both within research and clinical practice, it is of particular importance to direct attention to family members when evaluating the risk for affective disorders, as this may contribute to a better understanding of the role of within-family processes in the etiology and maintenance of the disorders, and help identify pathways through which resilience is promoted. This knowledge may ultimately contribute to more effective treatment, the early identification of affective problems, and possibly preventing new onset of disorder, severe disability and intensive treatment in those at the highest risk.

Acknowledgements: None., BACKGROUND: The identification of effective dementia prevention strategies is a major public health priority, due to the enormous and growing societal cost of this condition. Consumption of a Mediterranean diet (MedDiet) has been proposed to reduce dementia risk. However, current evidence is inconclusive and is typically derived from small cohorts with limited dementia cases. Additionally, few studies have explored the interaction between diet and genetic risk of dementia. METHODS: We used Cox proportional hazard regression models to explore the associations between MedDiet adherence, defined using two different scores (Mediterranean Diet Adherence Screener [MEDAS] continuous and Mediterranean diet Pyramid [PYRAMID] scores), and incident all-cause dementia risk in 60,298 participants from UK Biobank, followed for an average 9.1 years. The interaction between diet and polygenic risk for dementia was also tested. RESULTS: Higher MedDiet adherence was associated with lower dementia risk (MEDAS continuous: HR = 0.77, 95% CI = 0.65-0.91; PYRAMID: HR = 0.86, 95% CI = 0.73-1.02 for highest versus lowest tertiles). There was no significant interaction between MedDiet adherence defined by the MEDAS continuous and PYRAMID scores and polygenic risk for dementia. CONCLUSIONS: Higher adherence to a MedDiet was associated with lower dementia risk, independent of genetic risk, underlining the importance of diet in dementia prevention interventions.

Background: Traumatic experiences are associated with increased risk for major depressive disorder (MDD). This study sought to determine the extent that trauma exposure, depression polygenic risk scores (PRS), and their interaction are associated with MDD and individual depression symptoms. Methods: Data from 102,182 individuals from the large-scale UK Biobank population cohort was analysed. A series of regression analyses were conducted to estimate the association between trauma, depression PRS and 1) current depression, 2) lifetime MDD case-control status, 3) nine individual current depressive symptoms, and 4) thirteen individual symptoms experienced during a major depressive episode. Additive and multiplicative PRS-by-trauma interactions were also assessed. Results: Trauma and depression PRS were significantly associated with both current depression and lifetime MDD. A positive, additive interaction effect was observed on depression, but multiplicative interactions were not significant. Trauma exposure and depression PRS were associated with specific patterns of depression symptoms; Trauma was associated with low self-esteem, suicidal ideation, and atypical (but not typical) neurovegetative symptoms. Additive interaction effects were observed on six out of nine current depressive symptoms. Conclusions: Trauma exposure and genetic predisposition to depression may lead to particular symptomatology, which may contribute to the extreme clinical heterogeneity observed in individuals with major depression.

Psychiatric disorders are the consequence of complex interplay between genetic and environmental factors. Anhedonia, as a transdiagnostic symptom in multiple psychiatric disorders, has been linked to both genetic and environmental risk factors. However, the gene?environment interplay that contributes to anhedonia is poorly understood. The goal of this study was to investigate the associations between PRS-anhedonia and environmental risk exposures, and their interactions on phenotypic anhedonia and reward-related brain structure and function in two large population-based samples, UK Biobank and the ABCD study. We investigated gene?environment correlations and interactions in 19667 White European participants (55.30 � 7.49 years, 51.58% females) from UK Biobank and 9213 adolescents of diverse ancestries (9.90 � 0.62 years, 46.5% females) from the ABCD study separately. PRS-anhedonia was derived from an earlier genome-wide association study of state anhedonia. Many environmental risk factors such as parent depression and childhood trauma were included. Phenotypic anhedonia was assessed based on the subscale for depression in DSM-5. Brain characteristics included cortical thickness, surface area, cortical volume, sulcal depth, as well as brain activation during the Monetary Incentive Delay task and analyses were limited to priori regions of interest (seventeen reward-related brain structures). Spearman's rank correlation, logistic regression, linear regression and mixed linear regression were performed, with relevant covariates controlled for and supplementary analyses conducted for clarity. We found PRS-anhedonia was associated with multiple environmental exposures in the expected direction in both cohorts. Family conflict and school disengagement in the ABCD study significantly moderated the effect of PRS-anhedonia on the probability of parent-reported lifetime anhedonia. In addition, analyses on brain morphology and function found significant interactions of PRS-anhedonia with parent depression, adverse life events, family conflict, parent acceptance, and aggregate environmental risk scores. Interactive effects were found on surface area/ cortical volume/ functional activation in middle frontal cortex, cingulate cortex, caudate and pallium, among other reward- and non-reward-related brain structures, with detailed interaction patterns differing for environmental measures. These findings support the gene?environment interplay in psychiatry, especially effects of gene?environment interaction at the neurobiological level. Future efforts are needed to replicate these findings and to further understand the influence of environmental risk on genetic predispositions associated neurobiological vulnerability to mental disorders.

Background: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome-wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. Methods: To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent-trios with a low polygenic risk for the phenotype (discovery). We prioritized DNV-carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population-matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome-wide association data, expression, protein-protein-interactions), were used for final prioritization. Conclusion: In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re-sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations. Funding information: The present study was supported by the German Research Foundation (DFG)-Grants BE 3828/8-1, LU 1944/2-1, MA 2546/5-1, and LU1944/3-1. ACKNOWLEDGMENTS: The authors thank all patients, relatives, and control individuals for their participation. We thank the German support group for individuals with cleft lip and/or palate (Wolfgang Rosenthal Gesellschaft) for assistance with recruitment.We acknowledge the invaluable assistance of all clinical, laboratory, and bioinformatic personnel. The authors thank the Next Generation Sequencing Core Facility of the Medical Faculty of the University of Bonn for sequencing the samples that were used in this study. DbGaP datasets were accessed through dbGaP accession number phs000094.v1.p1 (Supplemental Acknowledgments). Finally, the authors thank the Genome Aggregation Database (gnomAD), and all groups that provided exome and genome variant data to this resource. A full list of gnomAD contributors is provided in the gnomAD flagship paper (Karczewski et al., 2020). Open Access funding enabled and organized by Projekt DEAL.

Anhedonia is a transdiagnostic symptom in mental disorders. Neuroimaging studies of anhedonia have implicated several brain structural correlates. Here we investigated whether anhedonia-related brain structural differences were present in early adolescents. 11,329 participants (aged 9 to 11 years, 5,897 males) from the population-based ABCD study were included. We investigated associations between anhedonia, PRS-anhedonia, and brain structural measures (CT, SA, sulcal depth, CV, subcortical volumes, FA and MD for white matter tracts). Linear mixed models were performed, adjusting for sex, age, age2, race/ethnicity, ICV, and assessment site, as well as brain hemisphere, family ID and first 10 principal genetic components where applicable. Compared to adolescents without anhedonia (N=10,283), those with present/past anhedonia (N=1,046) had smaller total SA and lower CV, and smaller regional SA/CV in the fusiform, inferior parietal cortex, middle temporal cortex and rostral middle frontal cortex (??=?-0.105 to -0.057). Higher PRS-anhedonia was associated with smaller total CV, total SA and total subcortical volume, as well as smaller SA in the superior frontal cortex and increased sulcal depth in the rostral middle frontal lobe (??=?-0.049 to 0.028). No associations with CT, subcortical volumes or diffusion tensor imaging measures of white matter integrity were found. Overall, anhedonia and PRS-anhedonia were associated with brain structural differences in adolescents, and some associations mirror our previous findings in adults. These results contribute to the understanding of a possible biological basis for adolescent anhedonia and may help to identify early neural biomarkers for mental disorders. Future work should assess how these associations change over time in longitudinal studies.

Refereed/Peer-reviewed Background: Across the life course, socioeconomic disadvantage disproportionately afflicts those with genetic predispositions to inflammatory diseases. We describe how socioeconomic disadvantage and polygenic risk for high BMI magnify the risk of obesity across childhood, and using causal analyses, explore the hypothetical impact of intervening on socioeconomic disadvantage to reduce adolescent obesity. Methods: Data were drawn from a nationally representative Australian birth cohort, with biennial data collection between 2004 and 2018 (research and ethics committee approved). We generated a polygenic risk score for BMI using published genome-wide association studies. We measured early-childhood disadvantage (age 2–3 years) with a neighbourhood census-based measure and a family-level composite of parent income, occupation, and education. We used generalised linear regression (Poisson-log link) to estimate the risk of overweight or obesity (BMI ≥85th percentile) at age 14–15 years for children with early-childhood disadvantage (quintiles 4–5) versus average (quintile 3) and least disadvantage (quintiles 1–2), for those with high and low polygenic risk separately. Findings: For 1607 children (n=796 female, n=811 male; 31% of the original cohort [N=5107]), polygenic risk and disadvantage were both associated with overweight or obesity; effects of disadvantage were more marked as polygenic risk increased. Of children with polygenic risk higher than the median (n=805), 37% of children living in disadvantage at age 2–3 years had an overweight or obese BMI by adolescence, compared with 26% of those with least disadvantage. For genetically vulnerable children, causal analyses indicated that early neighbourhood intervention to lessen disadvantage (to quintile 1–2) would reduce risk of adolescent overweight or obesity by 23% (risk ratio 0·77; 95% CI 0·57–1·04); estimates for improving family environments were similar (0·59; 0·43–0·80). Interpretation: Actions addressing socioeconomic disadvantage could mitigate polygenic risk for developing obesity. This study benefits from population-representative longitudinal data but is limited by sample size.

The aim of this study was to assess the acceptability and feasibility of offering risk-based breast cancer screening and its integration into regular clinical practice. A single-arm proof-of-concept trial was conducted with a sample of 387 women aged 40–50 years residing in the city of Lleida (Spain). The study intervention consisted of breast cancer risk estimation, risk communication and screening recommendations, and a follow-up. A polygenic risk score with 83 single nucleotide polymorphisms was used to update the Breast Cancer Surveillance Consortium risk model and estimate the 5-year absolute risk of breast cancer. The women expressed a positive attitude towards varying the frequency of breast screening according to individual risk and, especially, more frequently inviting women at higher-than-average risk. A lower intensity screening for women at lower risk was not as welcome, although half of the participants would accept it. Knowledge of the benefits and harms of breast screening was low, especially with regard to false positives and overdiagnosis. The women expressed a high understanding of individual risk and screening recommendations. The participants’ intention to participate in risk-based screening and satisfaction at 1-year were very high. This research was funded by INSTITUTO DE SALUD CARLOS III, grant number PI17/00834 and co-funded by Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”, with the support of the Lleida Biomedical Research Institute (IRBLleida) and the CERCA Programme/Generalitat de Catalunya. C.L.V received a grant from the Santander Predoc Program scholarship in 2020 as a predoctoral fellow at the University of Lleida (Agreement 87/2020 of the Consell de Govern, Universitat de Lleida, of 28 April 2020). The non-profit organization Oncolliga Lleida funded part of the genomic analyses for the breast cancer risk assessment. The publication of this article was partly funded by the non-profit women’s breast cancer support association ADIMA Lleida.

How do fathers’ and children’s internalising-associated genetics influence parenting and child internalising phenotypes? The full preregistration document with introduction, tables and figures, and references, can be found in the associated OSF project as a component.

Objective: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available.Methods: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership–Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses.Results: A higher polygenic resilience score was associated with a lower risk for PD (β = −0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.Interpretation: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270–278

Data availability: All ADNI data are made publicly available. Copyright © The Author(s) 2022. Psychoses in Alzheimer’s disease (AD) are associated with worse prognosis. Genetic vulnerability for schizophrenia (SCZ) may drive AD-related psychoses, yet its impact on brain constituents is still unknown. This study aimed to investigate the association between polygenic risk scores (PRSs) for SCZ and psychotic experiences (PE) and grey matter (GM) volume in patients with AD with (AD-PS) and without (AD-NP) psychosis. Clinical, genetic and T1-weighted MRI data for 800 participants were extracted from the ADNI database: 203 healthy controls, 121 AD-PS and 476 AD-NP. PRSs were calculated using a Bayesian approach and analysed at ten p-value thresholds. Standard voxel-based morphometry was used to process MRI data. Logistic regression models including both PRSs for SCZ and PE, and an AD-PRS were used to predict psychosis in AD. Associations between PRSs and GM volume were investigated in the whole sample and the three groups independently. Only the AD-PRS predicted psychosis in AD. Inconsistent associations between the SCZ-PRS and PE-PRS and GM volumes were found across groups. The SCZ-PRS was negatively associated with medio-temporal/subcortical volumes and positively with medial/orbitofrontal volumes in the AD-PS group. Only medio-temporal areas were more atrophic in the AD-PS group, while there was no significant correlation between psychosis severity and GM volume. Although not associated with psychoses, the SCZ-PRS was correlated with smaller medio-temporal and larger orbitofrontal volumes in AD-PS. Similar alterations have also been observed in SCZ patients. This finding suggest a possible disconnection between these regions associated with psychoses in more advanced AD. Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California.

This cohort study assesses whether recent stressful life events interact with genetic and environmental liability for schizophrenia in models of mental and physical health in the Dutch adult population.Key PointsQuestionIs the association of adulthood life stress with mental and physical health moderated by polygenic risk and exposome scores for schizophrenia? FindingsThis population-based cohort study of 6646 participants provides novel evidence of the associations of genetic and environmental liability for schizophrenia with mental health in the general population. Both genetic and environmental liability were associated with poor outcomes, particularly mental health, and the association between stressful life events and health outcomes was moderated by exposome score but not polygenic risk score for schizophrenia. MeaningThese findings showing an interaction between adulthood stressful life events and lifetime exposomic liability lend further support to the diathesis-stress model.ImportanceBoth adulthood stressful life events (SLEs) and liability for schizophrenia have been associated with poor mental and physical health in the general population, but their interaction remains to be elucidated to improve population-based health outcomes. ObjectiveTo test whether recent SLEs interact with genetic and environmental liability for schizophrenia in models of mental and physical health. Design, Setting, and ParticipantsThe Netherlands Mental Health Survey and Incidence Study-2 is a population-based prospective cohort study designed to investigate the prevalence, incidence, course, and consequences of mental disorders in the Dutch general population. Participants were enrolled from November 5, 2007, to July 31, 2009, and followed up with 3 assessments during 9 years. Follow-up was completed on June 19, 2018, and data were analyzed from September 1 to November 1, 2019. ExposuresRecent SLEs assessed at each wave and aggregate scores of genetic and environmental liability for schizophrenia: polygenic risk score for schizophrenia (PRS-SCZ) trained using the Psychiatric Genomics Consortium analysis results and exposome score for schizophrenia (ES-SCZ) trained using an independent data set. Main Outcomes and MeasuresIndependent and interacting associations of SLEs with ES-SCZ and PRS-SCZ on mental and physical health assessed at each wave using regression coefficients. ResultsOf the 6646 participants included at baseline, the mean (SD) age was 44.26 (12.54) years, and 3672 (55.25%) were female. The SLEs were associated with poorer physical health (B=-3.22 [95% CI, -3.66 to -2.79]) and mental health (B=-3.68 [95% CI, -4.05 to -3.32]). Genetic and environmental liability for schizophrenia was associated with poorer mental health (ES-SCZ: B=-3.07 [95% CI, -3.35 to -2.79]; PRS-SCZ: B=-0.93 [95% CI, -1.31 to -0.54]). Environmental liability was also associated with poorer physical health (B=-3.19 [95% CI, -3.56 to -2.82]). The interaction model showed that ES-SCZ moderated the association of SLEs with mental (B=-1.08 [95% CI, -1.47 to -0.69]) and physical health (B=-0.64 [95% CI, -1.11 to -0.17]), whereas PRS-SCZ did not. Several sensitivity analyses confirmed these results. Conclusions and RelevanceIn this study, schizophrenia liability was associated with broad mental health outcomes at the population level. Consistent with the diathesis-stress model, exposure to SLEs, particularly in individuals with high environmental liability for schizophrenia, was associated with poorer health. These findings underline the importance of modifiable environmental factors during the life span for population-based mental health outcomes.

Background The Psychosis Polyrisk Score (PPS) is a potential biomarker integrating non-purely genetic risk/protective factors for psychosis that may improve identification of individuals at risk and prediction of their outcomes at the individual subject level. Biomarkers that are easy to administer are direly needed in early psychosis to facilitate clinical implementation. This study digitally implements the PPS and pilots its feasibility of use in the real world. Methods The PPS was implemented digitally and prospectively piloted across individuals referred for a CHR-P assessment (n = 16) and healthy controls (n = 66). Distribution of PPS scores was further simulated in the general population. Results 98.8% of individuals referred for a CHR-P assessment and healthy controls completed the PPS assessment with only one drop-out. 96.3% of participants completed the assessment in under 15 min. Individuals referred for a CHR-P assessment had high PPS scores (mean = 6.2, SD = 7.23) than healthy controls (mean = −1.79, SD = 6.78, p

Receiving polygenic risk estimates of future disease through health care or direct-to-consumer companies is expected to become more common in the coming decades. However, only a limited number of studies have examined if such estimates might evoke an adverse psychosocial reaction in receivers. The present study utilized data from a sub-section of a personalized medicine project (the P5 study) that combines genomic and traditional health data to evaluate participants’ risk for certain common diseases. We investigated how communication of future disease risk estimates related to type 2 diabetes and coronary heart disease influenced respondents’ risk perception, self-efficacy, disease-related worry, and other emotions. A randomized controlled trial was conducted, where the experimental group (n = 714) received risk estimates based on traditional and polygenic risk factors and the control group (n = 649) based solely on traditional risk factors. On average, higher disease risk was associated with higher perceived risk (ps, p2 = 0.087–0.071), worry (ps p2 = 0.061–0.028), lower self-efficacy (p p2 = 0.012), less positive emotions (ps p2 = 0.042–0.005), and more negative emotions (ps p2 = 0.062–0.006). However, we found no evidence that adding the polygenic risk to complement the more traditional risk factors would induce any substantive psychosocial harm to the recipients (ps >0.06).

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8–17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

The polygenic risk score (PRS) allows for quantification of the relative contributions of genes and environment in population-based studies of mental health. We analyzed the impact of transdiagnostic schizophrenia PRS and measures of familial and environmental risk on the level of and change in general mental health (Short-Form-36 mental health) in the Netherlands Mental Health Survey and Incidence Study-2 general population sample, interviewed 4 times over a period of 9 years, yielding 8901 observations in 2380 individuals. Schizophrenia PRS, family history, somatic pain, and a range of environmental risks and social circumstances were included in the regression model of level of and change in mental health. We calculated the relative contribution of each (group of) risk factor(s) to the variance in (change in) mental health. In the combined model, familial and environmental factors explained around 17% of the variance in mental health, of which around 5% was explained by age and sex, 30% by social circumstances, 16% by pain, 22% by environmental risk factors, 24% by family history, and 3% by PRS for schizophrenia (PRS-SZ). Results were similar, but attenuated, for the model of mental health change over time. Childhood trauma and gap between actual and desired social status explained most of the variance. PRS for bipolar disorder, cross-disorder, and depression explained less variance in mental health than PRS-SZ. Polygenic risk for mental suffering, derived from significance-testing in massive samples, lacks impact in analyses focusing on prediction in a general population epidemiological setting. Social-environmental circumstances, particularly childhood trauma and perceived status gap, drive most of the attributable variation in population mental health.

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson’s Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson’s disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal–lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done. Electronic supplementary material The online version of this article (10.1007/s00401-020-02181-3) contains supplementary material, which is available to authorized users.

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. In general, polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.

BackgroundPsychosis spectrum disorder is a heterogeneous, multifactorial clinical phenotype, known to have a high heritability, only a minor portion of which can be explained by molecular measures of genetic variation. This study proposes that the identification of genetic variation underlying psychotic disorder may have suffered due to issues in the psychometric conceptualization of the phenotype. Here we aim to open a new line of research into the genetics of mental disorders by explicitly incorporating genes into symptom networks. Specifically, we investigate whether links between a polygenic risk score (PRS) for schizophrenia and measures of psychosis proneness can be identified in a network model.MethodsWe analyzed data from n = 2180 subjects (controls, patients diagnosed with a non-affective psychotic disorder, and the first-degree relatives of the patients). A network structure was computed to examine associations between the 42 symptoms of the Community Assessment of Psychic Experiences (CAPE) and the PRS for schizophrenia.ResultsThe resulting network shows that the PRS is directly connected to the spectrum of positive and depressive symptoms, with the items conspiracy and no future being more often located on predictive pathways from PRS to other symptoms.ConclusionsTo our knowledge, the current exploratory study provides a first application of the network framework to the field of behavior genetics research. This allows for a novel outlook on the investigation of the relations between genome-wide association study-based PRSs and symptoms of mental disorders, by focusing on the dependencies among variables.

Background While comorbidity of clinical high-risk for psychosis (CHR-P) status and social anxiety is well-established, it remains unclear how social anxiety and positive symptoms covary over time in this population. The present study aimed to determine whether there are more than one covariant trajectory of social anxiety and positive symptoms in the North American Prodrome Longitudinal Study cohort (NAPLS 2) and, if so, to test whether the different trajectory subgroups differ in terms of genetic and environmental risk factors for psychotic disorders and general functional outcome. Methods In total, 764 CHR individuals were evaluated at baseline for social anxiety and psychosis risk symptom severity and followed up every 6 months for 2 years. Application of group-based multi-trajectory modeling discerned three subgroups based on the covariant trajectories of social anxiety and positive symptoms over 2 years. Results One of the subgroups showed sustained social anxiety over time despite moderate recovery in positive symptoms, while the other two showed recovery of social anxiety below clinically significant thresholds, along with modest to moderate recovery in positive symptom severity. The trajectory group with sustained social anxiety had poorer long-term global functional outcomes than the other trajectory groups. In addition, compared with the other two trajectory groups, membership in the group with sustained social anxiety was predicted by higher levels of polygenic risk for schizophrenia and environmental stress exposures. Conclusions Together, these analyses indicate differential relevance of sustained v. remitting social anxiety symptoms in the CHR-P population, which in turn may carry implications for differential intervention strategies.

Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification.Methods To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (80\%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios (OR) and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22\%, compared to 40 and 74 for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26 for non-carriers and 98 for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve (AUC) in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups.

Objective: To estimate phenotypic and familial association between early-life injuries and attention-deficit/hyperactivity disorder (ADHD) and the genetic contribution to the association using polygenic risk score for ADHD (PRS-ADHD) and genetic correlation analyses.Methods: Children born in Denmark between 1995-2010 (n = 786,543) were followed from age 5 years until a median age of 14 years (interquartile range: 10-18 years). Using ICD-10 diagnoses, we estimated hazard ratios (HRs) and absolute risks of ADHD by number of hospital/emergency ward-treated injuries by age 5. In a subset of ADHD cases and controls born 1995 to 2005 who had genetic data available (n = 16,580), we estimated incidence rate ratios (IRRs) for the association between PRS-ADHD and number of injuries before age 5 and the genetic correlation between ADHD and any injury before age 5.Results: Injuries were associated with ADHD (HR = 1.61; 95% CI, 1.55-1.66) in males (HR = 1.59; 1.53-1.65) and females (HR = 1.65; 1.54-1.77), with a dose-response relationship with number of injuries. The absolute ADHD risk by age 15 was 8.4% (3+ injuries) vs 3.1% (no injuries). ADHD was also associated with injuries in relatives, with a stronger association in first- than second-degree relatives. PRS-ADHD was marginally associated with the number of injuries in the general population (IRR = 1.06; 1.00-1.14), with a genetic correlation of 0.53 (0.21-0.85).Conclusions: Early-life injuries in individuals and their relatives were associated with a diagnosis of ADHD. However, even in children with the most injuries, more than 90% were not diagnosed with ADHD by age 15. Despite a low positive predictive value and that the impact of unmeasured factors such as parental behavior remains unclear, results indicate that the association is partly explained by genetics, suggesting that early-life injuries may represent or herald early behavioral manifestations of ADHD.

BackgroundIn research and clinical practice, familial risk for depression and anxiety is often constructed as a simple Yes/No dichotomous family history (FH) indicator. However, this measure may not fully capture the liability to these conditions. This study investigated whether a continuous familial loading score (FLS), incorporating family- and disorder-specific characteristics (e.g. family size, prevalence of depression/anxiety), (i) is associated with a polygenic risk score (PRS) for major depression and with clinical/psychosocial vulnerabilities and (ii) still captures variation in clinical/psychosocial vulnerabilities after information on FH has been taken into account.MethodsData came from 1425 participants with lifetime depression and/or anxiety from the Netherlands Study of Depression and Anxiety. The Family Tree Inventory was used to determine FLS/FH indicators for depression and/or anxiety.ResultsPersons with higher FLS had higher PRS for major depression, more severe depression and anxiety symptoms, higher disease burden, younger age of onset, and more neuroticism, rumination, and childhood trauma. Among these variables, FH was not associated with PRS, severity of symptoms, and neuroticism. After regression out the effect of FH from the FLS, the resulting residualized measure of FLS was still associated with severity of symptoms of depression and anxiety, rumination, and childhood trauma.ConclusionsFamilial risk for depression and anxiety deserves clinical attention due to its associated genetic vulnerability and more unfavorable disease profile, and seems to be better captured by a continuous score that incorporates family- and disorder-specific characteristics than by a dichotomous FH measure.

IntroductionSuperAgers are individuals over age 80 with superior episodic memory, at a level consistent with individuals 20 to 30 years their junior and who seem to show resistance to age-related neurofibrillary degeneration. Here we examine whether low genetic risk for Alzheimer's disease (AD) contributes to SuperAgers' unusually high episodic memory performance in advanced age.MethodsThe AD polygenic hazard score (PHS) was calculated for each SuperAger and cognitively normal participant and compared between groups.ResultsA total of 37 SuperAgers (73% female, mean [standard deviation] 82.7 [2.8] years old) and 35 controls (54% female, 83.7 [4.3] years old) were included. There was no significant difference in the AD PHS between SuperAgers and cognitively normal controls.DiscussionUnusually successful cognitive aging cannot be simply explained by low polygenic risk for AD as assessed by common genetic variants. However, rare variants and common protective genetic factors may contribute to resistance or resilience.HighlightsSuperAging cannot be simply explained by low polygenic risk for Alzheimer's disease.Rare variants and common protective genetic factors may contribute to SuperAging.A protective factors polygenic score may uncover mechanisms for SuperAging.

Background: Mental health and cognitive achievement are partly heritable, highly polygenic, and associated with brain variations in structure and function. However, the underlying neural mechanisms remain unclear. Methods: We investigated the association between genetic predispositions to various mental health and cognitive traits and a large set of structural and functional brain measures from the UK Biobank (N = 36,799). We also applied linkage disequilibrium score regression to estimate the genetic correlations between various traits and brain measures based on genome-wide data. To decompose the complex association patterns, we performed a multivariate partial least squares model of the genetic and imaging modalities. Results: The univariate analyses showed that certain traits were related to brain structure (significant genetic correlations with total cortical surface area from rg = −0.101 for smoking initiation to rg = 0.230 for cognitive ability), while other traits were related to brain function (significant genetic correlations with functional connectivity from rg = −0.161 for educational attainment to rg = 0.318 for schizophrenia). The multivariate analysis showed that genetic predispositions to attention-deficit/hyperactivity disorder, smoking initiation, and cognitive traits had stronger associations with brain structure than with brain function, whereas genetic predispositions to most other psychiatric disorders had stronger associations with brain function than with brain structure. Conclusions: These results reveal that genetic predispositions to mental health and cognitive traits have distinct brain profiles.

Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75 973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (−3.47, −3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [−0.05 mg/dl per year, (−0.07, −0.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.

Cognitive impairment constitutes an important predictor of general functional outcomes in schizophrenia. Polygenic risk for schizophrenia has been linked to cognitive ability as well as brain activation during cognitive processing. Although sex differences have long been observed in schizophrenia patients, it is not known if genetic effects on cognitive phenotypes differ between males and females. Despite attempts to develop drugs that address the cognitive symptoms in schizophrenia or to investigate existing drugs with potential procognitive effects, there are currently no available medications that efficiently treat these symptoms in schizophrenia. The aim of this PhD project was to explore the genetic underpinnings of cognitive symptoms in schizophrenia, and to identify existing drugs that potentially could be used for repurposing to address these symptoms. We identified male-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning as well as brain activation during cognitive processing. Within gene networks, we identified a significant overlap between schizophrenia risk genes and genes associated with cognitive performance, and identified novel schizophrenia risk genes that are related to cognitive functioning. Utilizing gene networks incorporating gene expression data, we identified eight existing drugs that could potentially be used for repurposing to address the cognitive symptoms in schizophrenia, most of which have anti-inflammatory and neuroprotective effects. Using sex-specific gene expression data, we identified different repurposing candidates for male and female schizophrenia patients. In conclusion, the findings of this PhD project indicate that the effects of schizophrenia genetics on cognitive functioning are dependent on biological processes that differ between the sexes, and suggest that the cognitive symptoms in schizophrenia should be addressed by sex-specific pharmacological treatments. Uppgift om nummer i serie saknas i publikationen.

Previous research in patients with psychotic disorder has shown widespread abnormalities in brain activation during reward anticipation. Research at the level of subclinical psychotic experiences in individuals unexposed to antipsychotic medication is limited with inconclusive results. Therefore, brain activation during reward anticipation was examined in a larger sample of individuals with subclinical psychotic experiences (PE). Participants in the PE-group were included based on CAPE scores. A sample of emerging adults aged 16-26 years (n = 47) with PE and healthy controls (HC) (n = 40) underwent fMRI scanning. The Monetary Incentive Delay task was conducted with cues related to win, loss or neutral conditions. fMRI nonparametric tests were used to examine the reward versus neutral cue contrast. A significant main effect of the large win ((sic)3.00) > neutral contrast was found in both groups showing activation in many brain areas, including classic reward regions. Whole brain analysis on the group comparison regarding the large win > neutral contrast showed significantly decreased activation in the right insula, putamen and supramarginal gyrus in the PE-group compared to controls. There was no group difference in the hypothesized reward-related region. Decreased activation in the right insula, putamen and supramarginal gyrus during reward anticipation in individuals with PE may be consistent with altered processing of sensory information, related to decreased emotional valuing and motivational tendencies and/or altered motor-cognitive processes. The absence of group differences in striatal activation suggests that activation here is intact in the earliest stages of psychosis and may exhibit progressive deterioration in as the disease develops. (C) 2019 Elsevier B.V. and ECNP. All rights reserved.

Background: The prevalence of insomnia and hypersomnia in depressed individuals is substantially higher than that found in the general population. Unfortunately, these concurrent sleep problems can have profound effects on the disease course. Although the full biology of sleep remains to be elucidated, a recent genome-wide association (GWAS) of insomnia, and other sleep traits in over 1 million individuals was recently published and provides many promising hits for genetics of insomnia in a population-based sample.Methods: Using data from the largest available GWAS of insomnia and other sleep traits, we sought to test if sleep variable PRS scores derived from population-based studies predicted sleep variables in samples of depressed cases [Psychiatric Genomics Consortium - Major Depressive Disorder subjects (PGC MDD)]. A leave-one-out analysis was performed to determine the effects that each individual study had on our results.Results: The only significant finding was for insomnia, where p-value threshold, p = 0.05 was associated with insomnia in our PGC MDD sample (R2 = 1.75−3, p = 0.006).Conclusion: Our results reveal that p-value thresholds, which is in line with the fact that depression and insomnia are both polygenic disorders. To the best of our knowledge, this is the first study to investigate genetic overlap between the general population and a depression sample for insomnia, which has important treatment implications, such as leading to novel drug targets in future research efforts.

Funder: University of Bristol; Id: http://dx.doi.org/10.13039/501100000883, Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265, Funder: University Of Edinburgh; Id: http://dx.doi.org/10.13039/501100000848, BACKGROUND: Joint developmental trajectories of internalizing and externalizing problems show considerable heterogeneity; however, this can be parsed into a small number of meaningful subgroups. Doing so offered insights into risk factors that lead to different patterns of internalizing/externalizing trajectories. However, despite both domains of problems showing strong heritability, no study has yet considered genetic risks as predictors of joint internalizing/externalizing problem trajectories. METHODS: Using parallel process latent class growth analysis, we estimated joint developmental trajectories of internalizing and externalizing difficulties assessed across ages 4 to 16 using the Strengths and Difficulties Questionnaire. Multinomial logistic regression was used to evaluate a range of demographic, perinatal, maternal mental health, and child and maternal polygenic predictors of group membership. Participants included 11,049 children taking part in the Avon Longitudinal Study of Parents and Children. Polygenic data were available for 7,127 children and 6,836 mothers. RESULTS: A 5-class model was judged optimal: Unaffected, Moderate Externalizing Symptoms, High Externalizing Symptoms, Moderate Internalizing and Externalizing Symptoms and High Internalizing and Externalizing Symptoms. Male sex, lower maternal age, maternal mental health problems, maternal smoking during pregnancy, higher child polygenic risk scores for ADHD and lower polygenic scores for IQ distinguished affected classes from the unaffected class. CONCLUSIONS: While affected classes could be relatively well separated from the unaffected class, phenotypic and polygenic predictors were limited in their ability to distinguish between different affected classes. Results thus add to existing evidence that internalizing and externalizing problems have mostly shared risk factors.

Genética; Obesidad; Pérdida de peso Genetics; Obesity; Weight loss Genètica; Obesitat; Pèrdua de pes Around 30% of the patients that undergo bariatric surgery (BS) do not reach an appropriate weight loss. The OBEGEN study aimed to assess the added value of genetic testing to clinical variables in predicting weight loss after BS. A multicenter, retrospective, longitudinal, and observational study including 416 patients who underwent BS was conducted (Clinical.Trials.gov- NCT02405949). 50 single nucleotide polymorphisms (SNPs) from 39 genes were examined. Receiver Operating Characteristic (ROC) curve analysis were used to calculate sensitivity and specificity. Satisfactory response to BS was defined as at nadir excess weight loss >50%. A good predictive model of response [area under ROC of 0.845 (95% CI 0.805–0.880), p < 0.001; sensitivity 90.1%, specificity 65.5%] was obtained by combining three clinical variables (age, type of surgery, presence diabetes) and nine SNPs located in ADIPOQ, MC4R, IL6, PPARG, INSIG2, CNR1, ELOVL6, PLIN1 and BDNF genes. This predictive model showed a significant higher area under ROC than the clinical score (p = 0.0186). The OBEGEN study shows the key role of combining clinical variables with genetic testing to increase the predictability of the weight loss response after BS. This finding will permit us to implement a personalized medicine which will be associated with a more cost-effective clinical practice. This research was supported by grants from the “Pla Estratègic de Recerca i Innovació en Salut” (PERIS) 2016–2020 (SLT002/16/00497), the Instituto de Salud Carlos III (PI PI18/00964), Fondos FEDER “Una manera de hacer Europa”), and Menarini España. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) is an initiative of the Instituto Carlos III.

Personal Breast Cancer (BC) Risk Assessments (PBCRA) have potential to stratify women into clinically-actionable BC risk categories. As this could involve population-wide genomic testing, women’s attitudes to PBCRA and views on acceptable implementation platforms must be considered to ensure optimal population participation. We explored these issues with 31 women with different BC risk profiles through semi-structured focus group discussions or interviews. Inductive thematic coding of transcripts was performed. Subsequently, women listed factors that would impact on their decision to participate. Participants’ attitudes to PBCRA were positive. Identified themes included that PBCRA acceptance hinges on result actionability. Women value the ability to inform decision-making. Participants reported anxiety, stress, and genetic discrimination as potential barriers. The age at which PBCRA was offered, ease of access, and how results are returned held importance. Most women value the opportunity for PBCRA to inform increased surveillance, while highlighting hesitance to accept reduced surveillance as they find reassurance in regular screening. Women with BRCA pathogenic variants value the potential for PBCRA to identify a lower cancer risk and potentially inform delayed prophylactic surgery. This study highlights complexities in adopting advances in BC early detection, especially for current users who value existing processes as a social good.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal system. Omega-3 (ω3) fatty acids are polyunsaturated fatty acids (PUFAs) that are largely obtained from diet and have been speculated to decrease the inflammatory response that is involved in IBD; however, the causality of this association has not been established. A two-sample Mendelian randomization (MR) was used to assess genetic associations between 249 circulating metabolites measured in the UK Biobank as exposures and IBD as the outcome. The genome-wide association study summary level data for metabolite measurements and IBD were derived from large European ancestry cohorts. We observed ω3 fatty acids as a significant protective association with IBD, with multiple modes of MR evidence replicated in three IBD summary genetic datasets. The instrumental variables that were involved in the causal association of ω3 fatty acids with IBD highlighted an intronic SNP, rs174564, in FADS2, a protein engaged in the first step of alpha-linolenic acid desaturation leading to anti-inflammatory EPA and thence DHA production. A low ratio of ω3 to ω6 fatty acids was observed to be a causal risk factor, particularly for Crohn’s disease. ω3 fatty acid supplementation may provide anti-inflammatory responses that are required to attenuate inflammation that is involved in IBD.

BackgroundGenetic vulnerability to coronary heart disease (CHD) is well established, but little is known whether these effects are mediated or modified by equally well-established social determinants of CHD. We estimate the joint associations of the polygenetic risk score (PRS) for CHD and education on CHD events.MethodsThe data are from the 1992, 1997, 2002, 2007 and 2012 surveys of the population-based FINRISK Study including measures of social, behavioural and metabolic factors and genome-wide genotypes (N=26 203). Follow-up of fatal and non-fatal incident CHD events (N=2063) was based on nationwide registers.ResultsAllowing for age, sex, study year, region of residence, study batch and principal components, those in the highest quartile of PRS for CHD had strongly increased risk of CHD events compared with the lowest quartile (HR=2.26; 95% CI: 1.97 to 2.59); associations were also observed for low education (HR=1.58; 95% CI: 1.32 to 1.89). These effects were largely independent of each other. Adjustment for baseline smoking, alcohol use, body mass index, igh-density lipoprotein (HDL) and total cholesterol, blood pressure and diabetes attenuated the PRS associations by 10% and the education associations by 50%. We do not find strong evidence of interactions between PRS and education.ConclusionsPRS and education predict CHD events, and these associations are independent of each other. Both can improve CHD prediction beyond behavioural risks. The results imply that observational studies that do not have information on genetic risk factors for CHD do not provide confounded estimates for the association between education and CHD.

Background: Several rare and common variants are associated with Parkinson's disease. However, there is still an incomplete penetrance in the carriers of rare variants associated with Parkinson's disease. To address this issue, we investigated whether a PRS calculated from significant GWAS SNPs affects the penetrance of Parkinson's disease among carriers of rare monogenic variants in known Parkinson's disease genes and those with a family history. Methods: We calculated the PRS based on common variants and selected the carriers of rare monogenic variants by using the exome data from UK Biobank. Individuals were divided into three risk categories based on PRS: low (90%) risk groups. We then compared how PRS affects Parkinson\textquoterights disease risk among carriers of rare monogenic variants and those with family-history. Results: We observed a two-fold higher odds ratio for a carrier of a monogenic variant that had a high PRS (OR 4.07,95\% CI, 1.72-8.08) compared to carriers with a low PRS (OR 1.91, 95\% CI, 0.31-6.05). In the same line, carriers with a first-degree family history and with \>90\% PRS have even a higher risk of developing PD (OR 23.53, 95\%CI 5.39-71.54) compared to those with \

Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxy-genetic liability measures suggest gene-environment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRS-SCZ) and environmental exposures in 1,699 patients with a diagnosis of schizophrenia spectrum disorders and 1,542 unrelated controls with no lifetime history of a diagnosis of those disorders, we provide further evidence for gene-environment interaction in schizophrenia. Evidence was found for additive interaction of molecular genetic risk state for schizophrenia (binary mode of PRS-SCZ above 75% of the control distribution) with the presence of lifetime regular cannabis use and exposure to early-life adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of hearing impairment, season of birth (winter birth), and exposure to physical abuse or physical neglect in childhood. The sensitivity analyses replacing the a priori PRS-SCZ at 75% with alternative cut-points (50% and 25%) confirmed the additive interaction. Our results suggest that the etiopathogenesis of schizophrenia involves genetic underpinnings that act by making individuals more sensitive to the effects of some environmental exposures. ispartof: WORLD PSYCHIATRY vol:18 issue:2 pages:173-182 ispartof: location:Italy status: published

BackgroundWhereas genetic susceptibility increases the risk for major depressive disorder (MDD), non-genetic protective factors may mitigate this risk. In a large-scale prospective study of US Army soldiers, we examined whether trait resilience and/or unit cohesion could protect against the onset of MDD following combat deployment, even in soldiers at high polygenic risk.MethodsData were analyzed from 3079 soldiers of European ancestry assessed before and after their deployment to Afghanistan. Incident MDD was defined as no MDD episode at pre-deployment, followed by a MDD episode following deployment. Polygenic risk scores were constructed from a large-scale genome-wide association study of major depression. We first examined the main effects of the MDD PRS and each protective factor on incident MDD. We then tested the effects of each protective factor on incident MDD across strata of polygenic risk.ResultsPolygenic risk showed a dose–response relationship to depression, such that soldiers at high polygenic risk had greatest odds for incident MDD. Both unit cohesion and trait resilience were prospectively associated with reduced risk for incident MDD. Notably, the protective effect of unit cohesion persisted even in soldiers at highest polygenic risk.ConclusionsPolygenic risk was associated with new-onset MDD in deployed soldiers. However, unit cohesion – an index of perceived support and morale – was protective against incident MDD even among those at highest genetic risk, and may represent a potent target for promoting resilience in vulnerable soldiers. Findings illustrate the value of combining genomic and environmental data in a prospective design to identify robust protective factors for mental health.

There are now large-scale data on which common genetic variants confer risk for attention deficit hyperactivity disorder (ADHD). Here, we use mediation analyses to explore how cognitive and neural features might explain the association between common variant (polygenic) risk for ADHD and its core symptoms. In total, 544 participants participated (mean 21 years, 212 [39%] with ADHD], most with cognitive assessments, neuroanatomic imaging and imaging of white matter tract microstructure. We found that polygenic risk for ADHD was associated with symptoms of hyperactivity-impulsivity but not inattention. This association was mediated across multiple PRS thresholds by white matter microstructure, specifically by axial diffusivity of the right corona radiata, (maximum indirect effect β = −0.034 [CI. −0.065 to −0.01), by thickness of the left dorsomedial prefrontal [β = −0.029; CI −0.061 to −0.0047]) and area of the right lateral temporal cortex [β = 0.024; CI 0.0034 to 0.054]). Additionally, modest serial mediation was found, mapping a pathway from polygenic risk, to white matter microstructure of the anterior corona radiata, then cognition (working memory, focused attention), and finally to hyperactivity-impulsivity (working memory β = −0.014 [CI. −0.038 to −0.0026]; focused attention β = −0.011 [CI. −0.033 to −0.0017]). These mediation pathways were diagnostically specific and were not found for polygenic risk for ASD or schizophrenia. In conclusion, using a deeply phenotyped cohort, we delineate a pathway from polygenic risk for ADHD to hyperactive-impulsive symptoms through white matter microstructure, cortical anatomy and cognition.

Significance Systems-level interactions across physiological pathways, cell types, and tissues are core biological elements widely studied across diverse fields including evolution, systems biology, and model-organism genetics. However, they are essentially ignored in human genetics, and existing approaches fail to interpretably explain substantial complex trait heritability. Here, we propose the coordinated epistasis model of complex phenotypes that generalizes several recently proposed theoretical epistatic architectures of human traits. Broadly, coordination measures the degree to which epistasis effects act in concert with respect to marginal effects. It summarizes a dimension of polygenic effects orthogonal to parameters like heritability and standard estimates of epistasis., Interactions between genetic variants—epistasis—is pervasive in model systems and can profoundly impact evolutionary adaption, population disease dynamics, genetic mapping, and precision medicine efforts. In this work, we develop a model for structured polygenic epistasis, called coordinated epistasis (CE), and prove that several recent theories of genetic architecture fall under the formal umbrella of CE. Unlike standard epistasis models that assume epistasis and main effects are independent, CE captures systematic correlations between epistasis and main effects that result from pathway-level epistasis, on balance skewing the penetrance of genetic effects. To test for the existence of CE, we propose the even-odd (EO) test and prove it is calibrated in a range of realistic biological models. Applying the EO test in the UK Biobank, we find evidence of CE in 18 of 26 traits spanning disease, anthropometric, and blood categories. Finally, we extend the EO test to tissue-specific enrichment and identify several plausible tissue–trait pairs. Overall, CE is a dimension of genetic architecture that can capture structured, systemic forms of epistasis in complex human traits.

Background Both genetic and pre- and perinatal factors, including birth weight, have been implicated in the onset of attention deficit hyperactivity disorder (ADHD) traits among children. This study aimed to elucidate to what extent the genetic risk of ADHD moderates the association between birth weight and ADHD traits among Japanese children. Methods We conducted a longitudinal birth cohort study (Hamamatsu Birth Cohort for Mother and Children Study) to investigate the association of genetic risk for ADHD and low birth weight with ADHD traits among Japanese children. Out of 1258 children, we included 796 who completed follow-ups at 8 to 9 years of age. Birth weight was categorized as Results Birth weight of 2000–2499 g was not associated with ADHD traits. Birth weight under 2000 g was significantly associated with both inattention and hyperactivity. When accounting for higher and lower genetic risk for ADHD, only those with higher genetic risk and birth weight < 2000 g were associated with inattention (rate ratio [RR] 1.56, 95% CI 1.07–2.27) and hyperactivity (RR 1.87, 95% CI 1.14–3.06). Conclusions Birth weight under 2000 g, together with the genetic risk of ADHD, contributes to higher levels of ADHD traits among Japanese children aged 8 to 9 years. The suggested association between low birth weight and ADHD is confined to children with a genetic susceptibility to ADHD, indicating the relevance of genetic-environmental interactions in the etiology.

Maternal stress during pregnancy can cause alterations to the fetal hypothalamus–pituitary–adrenal (HPA) axis, a phenomenon known as fetal programming that may have lasting effects on offspring outcomes, including depression. Evidence suggests that these effects may vary with respect to the offspring's genetic risk. Nonetheless, few studies have examined these effects into adulthood, when risk for depression onset is highest. The present study builds upon the extant literature by examining the interaction of maternal prenatal perceived stress (MPPS) and offspring HPA-axis polygenic risk to predict offspring depression in early adulthood. A total of 381 mother–child dyads participated in a prospective, longitudinal study that spanned from pregnancy until offspring were 20 years of age. Polygenic risk was defined by a multilocus genetic profile score (MGPS) that reflected the additive risk of three HPA-axis candidate genes. The results indicated that the interaction of MPPS and HPA-axis MGPS confers risk for offspring depression at age 20, in line with the differential susceptibility model. This interaction may be specific to prenatal stress, as maternal stress during early childhood did not interact with genetic risk to predict depression. These findings provide the first evidence that genetic variants that are associated with the HPA axis may act in a polygenic, additive fashion to moderate the association between fetal programming and adult depression.

Background: Recently, genome-wide association studies have uncovered multiple genes that are statistically associated with schizophrenia and cognitive dysfunction. Among these genes is MIR137 that has been replicated as one of the strongest associations with schizophrenia and is an important regulator of many other schizophrenia-associated genes that play a critical role in neurodevelopment. Moreover, 1,016 genes have been discovered that are directly linked to cognitive functioning, which represents a core feature in schizophrenia. While these statistical associations contribute to elucidating the genetic architecture of schizophrenia and cognitive functioning, they cannot provide a plausible mechanism by which genes influence these phenotypes. It is likely that genetic variance contributes to psychosis and cognition by impacting brain structure, but this mechanism is not well established. Methods: To elucidate the path from genes to behavior via brain structure, we analyzed genetic, neuroimaging, clinical and neurocognitive data from three large independent imaging-genetics samples, including the cross-disorder samples MooDS comprising first degree relatives of patients with psychosis (N=426) and IntegraMent comprising patients with psychosis (N=316; together: “IntegraMooDS”), as well as the naturalistic adolescent sample IMAGEN (N=1,651). First, the influence of MIR137 genotype on cortical thickness, surface area and white matter fractional anisotropy in relatives and controls was investigated. Second, the intermediate role of cortical thickness and surface area in the relationship between polygenic scores for intelligence and cognitive functioning was examined in IMAGEN and IntegraMooDS. Results: First, we observed an interaction of MIR137 risk genotype and group (relatives vs controls) on white matter fractional anisotropy and cortical surface area. The relative group with MIR137 risk genotype had lower fractional anisotropy and surface area in similar regions as previous studies have reported in schizophrenia (PFWE < 0.05). The MIR137 risk genotype was associated with higher surface area in control subjects (PFWE < 0.05). Second, we observed a significant vertex-wise mediation in IntegraMooDS and IMAGEN, where the association between polygenic scores and cognitive functioning was partially mediated by surface area and cortical thickness in the prefrontal, anterior cingulate and medial temporal cortices (PFWE < 0.005). Discussion: MIR137 and polygenic scores for intelligence have a meaningful impact on brain structure in (sub-)clinical and healthy populations. These findings illustrate a biologically plausible mechanism where genetic variance modulates brain structure in areas that have been linked to both, psychosis and cognitive function. These results, if confirmed in longitudinal designs, can contribute to a better identification of people at high risk for psychosis., Genomweite Assoziationsstudien haben kürzlich eine Vielzahl von Genen identifiziert, die statistisch mit Schizophrenie und kognitiver Leistungsfähigkeit zusammenhängen. Darunter ist das Gen MIR137, welches als eines der stärksten Assoziationen mit Schizophrenie repliziert wurde. Neben MIR137 wurden 1016 Gene identifiziert, die signifikant mit kognitiver Leistungsfähigkeit assoziiert sind. Kognitive Dysfunktion stellt ein Kernmerkmal der Schizophrenie dar. In dieser Arbeit wurde der Zusammenhang zwischen MIR137 und Hirnstruktur bei Angehörigen von Menschen mit Psychose und der polygene Einfluss für kognitive Leistungsfähigkeit auf Hirnstruktur in zwei unabhängigen, klinischen und nicht-klinischen Stichproben untersucht. Beide Studien legen nahe, dass genetische Varianz durch den Einfluss auf Hirnstruktur zum Auftreten von Psychosen und Unterschieden in kognitiver Leistungsfähigkeit beiträgt. Methodik: Es wurden genetische, neuroimaging, klinische und neurokognitive Daten von drei großen unabhängigen Stichproben, einschließlich der Angehörigenstichprobe MooDS (N=426) und der Patientenstichprobe IntegraMent (N=316; zusammengefasst: “IntegraMooDS”), sowie der naturalistischen Jugendlichenstichprobe IMAGEN (N=1651) analysiert. Erstens wurde der Zusammenhang zwischen MIR137 Genotyp und kortikaler Dicke, kortikaler Oberfläche und der fraktionellen Anisotropie der weißen Substanz bei Angehörigen von Menschen mit Psychosen und Kontrollen untersucht. Zweitens wurde die mediierende Rolle von kortikaler Dicke und Oberfläche im Zusammenhang zwischen polygenen Scores für Intelligenz und kognitiver Leistungsfähigkeit in IMAGEN und IntegraMooDS untersucht. Ergebnisse: Erstens wurde eine Interaktion zwischen MIR137 Risikogenotyp und Gruppe (Angehörige vs Kontrollen) bei der fraktionellen Anisotropie der weißen Substanz und kortikaler Oberfläche (PFWE < 0,05) beobachtet. Angehörige mit Risikogenotyp hatten niedrigere fraktionelle Anisotropie und kortikale Oberfläche in ähnlichen Regionen wie frühere Studien an Patienten gezeigt haben (PFWE < 0,05). Zusätzlich war der MIR137 Risikogenotyp mit höherer kortikaler Oberfläche in Kontrollen assoziiert (PFWE < 0,05). Zweitens wurde eine signifikante vertex-weise Mediation in IntegraMooDS und IMAGEN beobachtet, in welcher der Zusammenhang zwischen polygenen Intelligenzscores und kognitiver Leistungsfähigkeit durch kortikale Dicke und Oberfläche mediiert wurde (PFWE < 0,005). Diskussion: MIR137 und polygene Intelligenzscores haben einen bedeutungsvollen Einfluss auf Hirnstruktur in (sub-)klinischen und gesunden Stichproben. Diese Ergebnisse veranschaulichen einen biologisch plausiblen Mechanismus, mithilfe dessen genetische Varianz Hirnstruktur in Regionen moduliert, die mit sowohl Psychose als auch kognitiver Leistungsfähigkeit assoziiert sind. Diese Ergebnisse können, wenn sie in longitudinalen Forschungsarbeiten validiert werden, zu einer verbesserten Identifikation von Psychosen beitragen.

Funding: AG and TFMA were supported by the Munich Cluster for Systems Neurology (SyNergy). AG 535 was supported by Fondazione Umberto Veronesi. SP is a Royal Society University Research fellow. BMM, CF, BSP and SEF are supported by the Max Planck Society. AW, BM and HK were funded by the Fraunhofer Society and the Max Planck Society within the ‘Pakt für Forschung und Innovation’. HK was also supported by LIFE – Leipzig Research Center for Civilization Diseases funded by means of the European Union; the European Regional Development Fund (ERDF); and the Free State of Saxony within the excellence initiative. FR is supported by Agence Nationale de la Recherche (ANR-06-NEURO-019-01, ANR-17-EURE-542 0017 IEC, ANR-10-IDEX-0001-02 PSL, ANR-11-BSV4-014-01), European Commission (LSHM-CT-2005-018696). TFMA was supported by the BMBF through the DIFUTURE consortium of the Medical Informatics Initiative Germany (grant 01ZZ1804A) and by the European Union’s Horizon 2020 Research and Innovation Programme (grant MultipleMS, EU RIA 733161). Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p

The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project is funded by grant agreement HEALTH-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework Programme., Aas, M; Alameda, L; Di Forti, M; Quattrone, D; Dazzan, P; Trotta, A; Ferraro, L; Rodriguez, V; Vassos, E; Sham, P; Tripoli, G; La Cascia, C; La Barbera, D; Tarricone, I; Muratori, R; Berardi, D; Lasalvia, A; Tosato, S; Szoke, A; Llorca, PM; Arango, C; Tortelli, A; de Haan, L; Velthorst, E; Bobes, J; Bernardo, M; Sanjuan, J; Santos, JL; Arrojo, M; Del-Ben, CM; Menezes, PR; Selten, JP; Jones, PB; Jongsma, HE; Kirkbride, JB; Rutten, BPF; van Os, J; Gayer-Anderson, C; Murray, RM; Morgan, C

IntroductionPolygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population.Material and MethodsAnonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-fold cross-validation search were conducted, to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African were compared using the same cross-validated approach.ResultsThree SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53).ConclusionsWe identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans and Asians. A strategy of building on established statistical models might benefit ancestral groups generally under-represented in genome-wide association studies.