Early maturation and substance use across adolescence and young adulthood : A longitudinal study of Finnish twins

Early maturation, indexed by pubertal development (PD), has been associated with earlier initiation and greater frequency of adolescent substance use, but this relationship may be biased by confounding factors and effects that change across development. Using a population-based Finnish twin sample (N = 3,632 individuals), we conducted twin modeling and multilevel structural equation modeling of the relationship between PD and substance use at ages 12-22. Shared environmental factors contributed to early PD and heavier substance use for females. Biological father absence was associated with early PD for boys but not girls, and did not account for the relationship between PD and substance use. The association between early PD and heavier substance use was partially due to between-family confounds, although early PD appeared to qualitatively alter long-term trajectories for some substances (nicotine), but not others (alcohol). Mediation by peer and parental factors did not explain this relationship within families. However, higher peer substance use and lower parental monitoring were themselves associated with heavier substance use, strengthening the existing evidence for these factors as targets for prevention/intervention efforts. Early maturation was not supported as a robust determinant of alcohol use trajectories in adolescence and young adulthood, but may require longer term follow-up. Subtle effects of early PD on nicotine and illicit drug use trajectories throughout adolescence and adulthood merit further investigation.Peer reviewe

Molecular Genetic Influences on Normative and Problematic Alcohol Use in a Population-Based Sample of College Students

Background: Genetic factors impact alcohol use behaviors and these factors may become increasingly evident during emerging adulthood. Examination of the effects of individual variants as well as aggregate genetic variation can clarify mechanisms underlying risk. Methods: We conducted genome-wide association studies (GWAS) in an ethnically diverse sample of college students for three quantitative outcomes including typical monthly alcohol consumption, alcohol problems, and maximum number of drinks in 24 h. Heritability based on common genetic variants (h2SNP) was assessed. We also evaluated whether risk variants in aggregate were associated with alcohol use outcomes in an independent sample of young adults. Results: Two genome-wide significant markers were observed: rs11201929 in GRID1 for maximum drinks in 24 h, with supportive evidence across all ancestry groups; and rs73317305 in SAMD12 (alcohol problems), tested only in the African ancestry group. The h2SNP estimate was 0.19 (SE = 0.11) for consumption, and was non-significant for other outcomes. Genome-wide polygenic scores were significantly associated with alcohol outcomes in an independent sample. Conclusions: These results robustly identify genetic risk for alcohol use outcomes at the variant level and in aggregate. We confirm prior evidence that genetic variation in GRID1impacts alcohol use, and identify novel loci of interest for multiple alcohol outcomes in emerging adults. These findings indicate that genetic variation influencing normative and problematic alcohol use is, to some extent, convergent across ancestry groups. Studying college populations represents a promising avenue by which to obtain large, diverse samples for gene identification

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

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

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

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

Association of genetic liability to psychotic experiences with neuropsychotic disorders and traits

Importance: Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5% to 10% of the general population, although only a small proportion develop psychotic disorders such as schizophrenia. Studying the genetic causes of psychotic experiences in the general population, and its association with the genetic causes of other disorders, may increase the understanding of their pathologic significance. Objectives: To determine whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits and to identify genetic loci associated with psychotic experiences. Design, Setting and Participants: Analyses of genetic correlation, polygenic risk scores, and copy number variation were performed using data from participants in the UK Biobank from April 1, 2018, to March 20, 2019, to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. Genome-wide association studies of psychotic experience phenotypes were conducted to identify novel genetic loci. Participants in the final analyses after exclusions included 6123 individuals reporting any psychotic experience, 2143 individuals reporting distressing psychotic experiences, and 3337 individuals reporting multiple occurrences of psychotic experiences. A total of 121 843 individuals who did not report a psychotic experience formed the comparator group. Individuals with a psychotic disorder were excluded from all analyses. Main Outcomes and Measures: Genetic associations with psychotic experience phenotypes. Results: The study included a total of 127 966 participants (56.0% women and 44.0% men; mean [SD] age, 64.0 [7.6] years). Psychotic experiences were genetically correlated with major depressive disorder, schizophrenia, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Analyses of polygenic risk scores identified associations between psychotic experiences and genetic liability for major depressive disorder, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Individuals reporting psychotic experiences had an increased burden of copy number variations previously associated with schizophrenia (odds ratio [OR], 2.04; 95% CI, 1.39-2.98; P = 2.49 × 10−4) and neurodevelopmental disorders more widely (OR, 1.75; 95% CI, 1.24-2.48; P = 1.41 × 10−3). Genome-wide association studies identified 4 significantly associated loci, including a locus in Ankyrin-3 (ANK3 [GenBank NM_020987]) (OR, 1.16; 95% CI, 1.10-1.23; P = 3.06 × 10−8) with any psychotic experience, and a locus in cannabinoid receptor 2 gene (CNR2 [GenBank NM_001841]) (OR, 0.66; 95% CI, 0.56-0.78; P = 3.78 × 10−8) with distressing psychotic experiences. The genome-wide association study of any psychotic experience had a low single-nucleotide polymorphism–based heritability estimate (h2 = 1.71%; 95% CI, 1.02%-2.40%). Conclusions and Relevance: A large genetic association study of psychotic experiences from the population-based UK Biobank sample found support for a shared genetic liability between psychotic experiences and schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders

Genetic mapping and evolutionary analysis of human-expanded cognitive networks

Cognitive brain networks such as the default-mode network (DMN), frontoparietal network, and salience network, are key functional networks of the human brain. Here we show that the rapid evolutionary cortical expansion of cognitive networks in the human brain, and most pronounced the DMN, runs parallel with high expression of human-accelerated genes (HAR genes). Using comparative transcriptomics analysis, we present that HAR genes are differentially more expressed in higher-order cognitive networks in humans compared to chimpanzees and macaques and that genes with high expression in the DMN are involved in synapse and dendrite formation. Moreover, HAR and DMN genes show significant associations with individual variations in DMN functional activity, intelligence, sociability, and mental conditions such as schizophrenia and autism. Our results suggest that the expansion of higher-order functional networks subserving increasing cognitive properties has been an important locus of genetic changes in recent human brain evolution

Unpacking the behavioural components and delivery features of early childhood obesity prevention interventions in the TOPCHILD Collaboration: a systematic review and intervention coding protocol.

INTRODUCTION: Little is known about how early (eg, commencing antenatally or in the first 12 months after birth) obesity prevention interventions seek to change behaviour and which components are or are not effective. This study aims to (1) characterise early obesity prevention interventions in terms of target behaviours, delivery features and behaviour change techniques (BCTs), (2) explore similarities and differences in BCTs used to target behaviours and (3) explore effectiveness of intervention components in preventing childhood obesity. METHODS AND ANALYSIS: Annual comprehensive systematic searches will be performed in Epub Ahead of Print/MEDLINE, Embase, Cochrane (CENTRAL), CINAHL, PsycINFO, as well as clinical trial registries. Eligible randomised controlled trials of behavioural interventions to prevent childhood obesity commencing antenatally or in the first year after birth will be invited to join the Transforming Obesity in CHILDren Collaboration. Standard ontologies will be used to code target behaviours, delivery features and BCTs in both published and unpublished intervention materials provided by trialists. Narrative syntheses will be performed to summarise intervention components and compare applied BCTs by types of target behaviours. Exploratory analyses will be undertaken to assess effectiveness of intervention components. ETHICS AND DISSEMINATION: The study has been approved by The University of Sydney Human Research Ethics Committee (project no. 2020/273) and Flinders University Social and Behavioural Research Ethics Committee (project no. HREC CIA2133-1). The study's findings will be disseminated through peer-reviewed publications, conference presentations and targeted communication with key stakeholders. PROSPERO REGISTRATION NUMBER: CRD42020177408

Transforming Obesity Prevention for CHILDren (TOPCHILD) Collaboration: protocol for a systematic review with individual participant data meta-analysis of behavioural interventions for the prevention of early childhood obesity.

INTRODUCTION: Behavioural interventions in early life appear to show some effect in reducing childhood overweight and obesity. However, uncertainty remains regarding their overall effectiveness, and whether effectiveness differs among key subgroups. These evidence gaps have prompted an increase in very early childhood obesity prevention trials worldwide. Combining the individual participant data (IPD) from these trials will enhance statistical power to determine overall effectiveness and enable examination of individual and trial-level subgroups. We present a protocol for a systematic review with IPD meta-analysis to evaluate the effectiveness of obesity prevention interventions commencing antenatally or in the first year after birth, and to explore whether there are differential effects among key subgroups. METHODS AND ANALYSIS: Systematic searches of Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo and trial registries for all ongoing and completed randomised controlled trials evaluating behavioural interventions for the prevention of early childhood obesity have been completed up to March 2021 and will be updated annually to include additional trials. Eligible trialists will be asked to share their IPD; if unavailable, aggregate data will be used where possible. An IPD meta-analysis and a nested prospective meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome will be body mass index z-score at age 24±6 months using WHO Growth Standards, and effect differences will be explored among prespecified individual and trial-level subgroups. Secondary outcomes include other child weight-related measures, infant feeding, dietary intake, physical activity, sedentary behaviours, sleep, parenting measures and adverse events. ETHICS AND DISSEMINATION: Approved by The University of Sydney Human Research Ethics Committee (2020/273) and Flinders University Social and Behavioural Research Ethics Committee (HREC CIA2133-1). Results will be relevant to clinicians, child health services, researchers, policy-makers and families, and will be disseminated via publications, presentations and media releases. PROSPERO REGISTRATION NUMBER: CRD42020177408