GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis.

Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson's disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

Genome-wide association study identifies new loci associated with OCD.

To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28% but finding only one significant SNP. A substantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways mediating the susceptibility to OCD. We conducted a GWAS meta-analysis with a 2-3-fold increase in case sample size (OCD cases: N = 37,015, controls: N = 948,616) compared to the last OCD GWAS, including six previously published cohorts (OCGAS, IOCDF-GC, IOCDF-GC-trio, NORDiC-nor, NORDiC-swe, and iPSYCH) and unpublished self-report data from 23andMe Inc. We explored the genetic architecture of OCD by conducting gene-based tests, tissue and celltype enrichment analyses, and estimating heritability and genetic correlations with 74 phenotypes. To examine a potential heterogeneity in our data, we conducted multivariable GWASs with MTAG. We found support for 15 independent genome-wide significant loci (14 new) and 79 protein-coding genes. Tissue enrichment analyses implicate multiple cortical regions, the amygdala, and hypothalamus, while cell type analyses yielded 12 cell types linked to OCD (all neurons). The SNP-based heritability of OCD was estimated to be 0.08. Using MTAG we found evidence for specific genetic underpinnings characteristic of different cohort-ascertainment and identified additional significant SNPs. OCD was genetically correlated with 40 disorders or traits-positively with all psychiatric disorders and negatively with BMI, age at first birth and multiple autoimmune diseases. The GWAS meta-analysis identified several biologically informative genes as important contributors to the aetiology of OCD. Overall, we have begun laying the groundwork through which the biology of OCD will be understood and described.

Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions.

The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer's disease, bipolar disorder, and Tourette's syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.

A Burden of Rare Copy Number Variants in Obsessive-Compulsive Disorder.

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from large, rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2,248 deeply phenotyped OCD cases and 3,608 unaffected controls from Sweden and Norway. We found that in general cases carry an elevated burden of large (>30kb, at least 15 probes) CNVs (OR=1.12, P=1.77×10-3). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02-0.11, P=2.58×10-3). This signal was largely driven by CNVs overlapping protein-coding regions (OR=1.19, P=3.08×10-4), particularly deletions impacting loss-of-function intolerant genes (pLI>0.995, OR=4.12, P=2.54×10-5). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation P = 2.60×10-3). In cases where sufficient clinical data were available (n=1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (P<0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (P=0.02). The results demonstrate a contribution of large, rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.

ADHD medication discontinuation and persistence across the lifespan: a retrospective observational study using population-based databases.

BACKGROUND: Although often intended for long-term treatment, discontinuation of medication for ADHD is common. However, cross-national estimates of discontinuation are missing due to the absence of standardised measures. The aim of this study was to determine the rate of ADHD treatment discontinuation across the lifespan and to describe similarities and differences across countries to guide clinical practice. METHODS: We did a retrospective, observational study using population-based databases from eight countries and one Special Administrative Region (Australia, Denmark, Hong Kong, Iceland, the Netherlands, Norway, Sweden, the UK, and the USA). We used a common analytical protocol approach and extracted prescription data to identify new users of ADHD medication. Eligible individuals were aged 3 years or older who had initiated ADHD medication between 2010 and 2020. We estimated treatment discontinuation and persistence in the 5 years after treatment initiation, stratified by age at initiation (children [age 4-11 years], adolescents [age 12-17 years], young adults [age 18-24 years], and adults [age ≥25 years]) and sex. Ethnicity data were not available. FINDINGS: 1 229 972 individuals (735 503 [60%] males, 494 469 females [40%]; median age 8-21 years) were included in the study. Across countries, treatment discontinuation 1-5 years after initiation was lowest in children, and highest in young adults and adolescents. Within 1 year of initiation, 65% (95% CI 60-70) of children, 47% (43-51) of adolescents, 39% (36-42) of young adults, and 48% (44-52) of adults remained on treatment. The proportion of patients discontinuing was highest between age 18 and 19 years. Treatment persistence for up to 5 years was higher across countries when accounting for reinitiation of medication; at 5 years of follow-up, 50-60% of children and 30-40% of adolescents and adults were covered by treatment in most countries. Patterns were similar across sex. INTERPRETATION: Early medication discontinuation is prevalent in ADHD treatment, particularly among young adults. Although reinitiation of medication is common, treatment persistence in adolescents and young adults is lower than expected based on previous estimates of ADHD symptom persistence in these age groups. This study highlights the scope of medication treatment discontinuation and persistence in ADHD across the lifespan and provides new knowledge about long-term ADHD medication use. FUNDING: European Union Horizon 2020 Research and Innovation Programme.

Maternal Fiber Intake During Pregnancy and Development of Attention-Deficit/Hyperactivity Disorder Symptoms Across Childhood: The Norwegian Mother, Father, and Child Cohort Study.

BACKGROUND: Epidemiological studies suggest that maternal diet quality during pregnancy may influence the risk of neurodevelopmental disorders in offspring. Here, we investigated associations between maternal intake of dietary fiber and attention-deficit/hyperactivity disorder (ADHD) symptoms in early childhood. METHODS: We used longitudinal data of up to 21,852 mother-father-child trios (49.2% female offspring) from MoBa (the Norwegian Mother, Father, and Child Cohort Study). The relationships between maternal fiber intake during pregnancy and offspring ADHD symptoms at ages 3, 5, and 8 years were examined using 1) multivariate regression (overall levels of ADHD symptoms), 2) latent class analysis (subclasses of ADHD symptoms by sex at each age), and 3) latent growth curves (longitudinal change in offspring ADHD symptoms). Covariates were ADHD polygenic scores in child and parents, total energy intake and energy-adjusted sugar intake, parental ages at birth of the child, and sociodemographic factors. RESULTS: Higher maternal prenatal fiber intake was associated with lower offspring ADHD symptom scores at all ages (Bage3 = -0.14 [95% CI, -0.18 to -0.10]; Bage5 = -0.14 [95% CI, -0.19 to -0.09]; Bage8 = -0.14 [95% CI, -0.20 to -0.09]). Of the derived low/middle/high subclasses of ADHD symptoms, fiber was associated with lower risk of belonging to the middle subclass for boys and girls and to the high subclass for girls only (middle: odds ratioboys 0.91 [95% CI, 0.86 to 0.97]/odds ratiogirls 0.86 [95% CI, 0.81 to 0.91]; high: odds ratiogirls 0.82 [95% CI, 0.72 to 0.94]). Maternal fiber intake and rate of change in child ADHD symptoms across ages were not associated. CONCLUSIONS: Low prenatal maternal fiber intake may increase symptom levels of ADHD in offspring during childhood, independently of genetic predisposition to ADHD, unhealthy dietary exposures, and sociodemographic factors.

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura.

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.

Neurobiological mechanisms of ECT and TMS treatment in depression: study protocol of a multimodal magnetic resonance investigation.

BACKGROUND: Noninvasive neurostimulation treatments are increasingly being used to treat major depression, which is a common cause of disability worldwide. While electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are both effective in treating depressive episodes, their mechanisms of action are, however, not completely understood. ECT is given under general anesthesia, where an electrical pulse is administered through electrodes placed on the patient's head to trigger a seizure. ECT is used for the most severe cases of depression and is usually not prescribed before other options have failed. With TMS, brain stimulation is achieved through rapidly changing magnetic fields that induce electric currents underneath a ferromagnetic coil. Its efficacy in depressive episodes has been well documented. This project aims to identify the neurobiological underpinnings of both the effects and side effects of the neurostimulation techniques ECT and TMS. METHODS: The study will utilize a pre-post case control longitudinal design. The sample will consist of 150 subjects: 100 patients (bipolar and major depressive disorder) who are treated with either ECT (N = 50) or TMS (N = 50) and matched healthy controls (N = 50) not receiving any treatment. All participants will undergo multimodal magnetic resonance imaging (MRI) as well as neuropsychological and clinical assessments at multiple time points before, during and after treatment. Arterial spin labeling MRI at baseline will be used to test whether brain perfusion can predict outcomes. Signs of brain disruption, potentiation and rewiring will be explored with resting-state functional MRI, magnetic resonance spectroscopy and multishell diffusion weighted imaging (DWI). Clinical outcome will be measured by clinician assessed and patient reported outcome measures. Memory-related side effects will be investigated, and specific tests of spatial navigation to test hippocampal function will be administered both before and after treatment. Blood samples will be stored in a biobank for future analyses. The observation time is 6 months. Data will be explored in light of the recently proposed disrupt, potentiate and rewire (DPR) hypothesis. DISCUSSION: The study will contribute data and novel analyses important for our understanding of neurostimulation as well as for the development of enhanced and more personalized treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05135897.

The effects of phenylalanine and tyrosine levels on dopamine production in rat PC12 cells. Implications for treatment of phenylketonuria, tyrosinemia type 1 and comorbid neurodevelopmental disorders.

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, resulting in phenylalanine accumulation and impaired tyrosine production. In Tyrosinemia type 1 (TYRSN1) mutations affect fumarylacetoacetate hydrolase, leading to accumulation of toxic intermediates of tyrosine catabolism. Treatment of TYRSN1 with nitisinone results in extreme tissue levels of tyrosine. Although PKU and TYRSN1 have opposite effects on tyrosine levels, both conditions have been associated with neuro-psychiatric symptoms typically present in ADHD, possibly indicating an impaired dopamine (DA) synthesis. However, concrete in vivo data on the possible molecular basis for disrupted DA production under disease mimicking conditions have been lacking. In pursuit to uncover associated molecular mechanisms, we exposed an established, DA producing cell line (PC12) to different concentrations of phenylalanine and tyrosine in culture media. We measured the effects on viability, proteomic composition, tyrosine, DA and tyrosine hydroxylase (TH) levels and TH phosphorylation. TH catalyzes the rate-limiting step in DA synthesis. High extracellular levels of phenylalanine depleted cells of intracellular tyrosine and DA. Compared to physiological levels (75 µM), either low (35 µM) or high concentrations of tyrosine (275 or 835 µM) decreased cellular DA, TH protein, and its phosphorylation levels. Using deep proteomic analysis, we identified multiple proteins, biological processes and pathways that were altered, including enzymes and transporters involved in amino acid metabolism. Using this information and published data, we developed a mathematical model to predict how extracellular levels of aromatic amino acids can affect the cellular synthesis of DA via different mechanisms. Together, these data provide new information about the normal regulation of neurotransmitter synthesis and how this may be altered in neurometabolic disorders, such as PKU and TYRSN1, with implications for the treatment of cognitive symptoms resulting from comorbid neurodevelopmental disorders.

Use of big data and machine learning algorithms to extract possible treatment targets in neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) impact multiple aspects of an individual's functioning, including social interactions, communication, and behaviors. The underlying biological mechanisms of NDDs are not yet fully understood, and pharmacological treatments have been limited in their effectiveness, in part due to the complex nature of these disorders and the heterogeneity of symptoms across individuals. Identifying genetic loci associated with NDDs can help in understanding biological mechanisms and potentially lead to the development of new treatments. However, the polygenic nature of these complex disorders has made identifying new treatment targets from genome-wide association studies (GWAS) challenging. Recent advances in the fields of big data and high-throughput tools have provided radically new insights into the underlying biological mechanism of NDDs. This paper reviews various big data approaches, including classical and more recent techniques like deep learning, which can identify potential treatment targets from GWAS and other omics data, with a particular emphasis on NDDs. We also emphasize the increasing importance of explainable and causal machine learning (ML) methods that can aid in identifying genes, molecular pathways, and more complex biological processes that may be future targets of intervention in these disorders. We conclude that these new developments in genetics and ML hold promise for advancing our understanding of NDDs and identifying novel treatment targets.

Risk factors of suicidal spectrum behaviors in adults and adolescents with attention-deficit / hyperactivity disorder - a systematic review.

INTRODUCTION: Adolescents and adults with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of suicidal spectrum behaviors (SSBs). However, there is limited knowledge about risk factors triggering SSBs in this group of people. OBJECTIVE: To explore published literature concerning factors that may increase the risk of SSBs in adults and adolescents with ADHD. METHODS: A systematic literature search following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted on 22nd of February 2022 using the Ovid MEDLINE and Web of Science databases. Three categories of search terms were used: (1) self-harm, self-injury, self-mutilation, suicide, self-poisoning; (2) adults, adolescents; and (3) attention-deficit hyperactivity disorder/ADHD. Studies with data concerning mediating factors of SSBs in relation to a clinical diagnosis of ADHD in participants above 16 years of age were included. RESULTS: The literature search identified 604 articles, of which 40 were included in the final study selection. Factors found to increase the likelihood of SSBs included ADHD symptom severity and persistence, female gender, family history of ADHD, childhood and parental influences, and social functioning. Even when adjusting for psychiatric comorbidities, most studies showed that adults and adolescents with ADHD have an elevated risk of SSBs. CONCLUSION: This systematic review has documented that several demographic and clinical features are associated with an increased risk of SSBs in adolescents and adults with ADHD. Notably, ADHD emerges as an independent risk factor for SSBs. This information ought to have clinical implications in terms of screening and suicide prevention strategies. Further longitudinal studies are needed to investigate the outcome of preventive strategies in individuals along the full spectrum of ADHD symptom severity.

Case report: ADHD and prognosis in tyrosinemia type 1.

Neurometabolic disorders such as tyrosinemia type 1 (TYRSN1) may interfere with brain metabolism and show symptoms of attention-deficit hyperactivity disorder (ADHD) in patients treated with the enzyme inhibitor nitisinone [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, NTBC]. It has been reported that ADHD treatment improves treatment compliance, which is imperative for the long-term prognosis of patients with TYRSN1. In this study, we report the case of a male patient who was diagnosed with TYRSN1 at 3 months of age and was subsequently treated with NTBC, restricted protein intake, and amino acids supplementation. At 7 years of age, he was referred for neuropsychiatric assessment, diagnosed with ADHD, and treated with methylphenidate. The effects of the treatment were monitored via parental interviews, questionnaires covering ADHD symptoms, and a continuous performance test. A reduction in ADHD symptoms, particularly inattentiveness, was observed across all measures. The early identification of ADHD and the treatment of neurometabolic disorders, such as TYRSN1, may be important from a lifetime perspective as this may improve the prognosis of the medical condition as well.

Potassium channels in behavioral brain disorders. Molecular mechanisms and therapeutic potential: A narrative review.

Potassium channels (K+-channels) selectively control the passive flow of potassium ions across biological membranes and thereby also regulate membrane excitability. Genetic variants affecting many of the human K+-channels are well known causes of Mendelian disorders within cardiology, neurology, and endocrinology. K+-channels are also primary targets of many natural toxins from poisonous organisms and drugs used within cardiology and metabolism. As genetic tools are improving and larger clinical samples are being investigated, the spectrum of clinical phenotypes implicated in K+-channels dysfunction is rapidly expanding, notably within immunology, neurosciences, and metabolism. K+-channels that previously were considered to be expressed in only a few organs and to have discrete physiological functions, have recently been found in multiple tissues and with new, unexpected functions. The pleiotropic functions and patterns of expression of K+-channels may provide additional therapeutic opportunities, along with new emerging challenges from off-target effects. Here we review the functions and therapeutic potential of K+-channels, with an emphasis on the nervous system, roles in neuropsychiatric disorders and their involvement in other organ systems and diseases.

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality.

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Electroconvulsive therapy triggers a reversible decrease in brain N-acetylaspartate.

Introduction: Based on previous research on electroconvulsive therapy (ECT) we have proposed a model where disruption, potentiation, and rewiring of brain networks occur in sequence and serve as the underlying therapeutic mechanism of ECT. This model implies that a temporary disturbance of neuronal networks (disruption) is followed by a trophic effect (potentiation), which enables the rewiring of neuronal circuits to a more euthymic functioning brain. We hypothesized that disruption of neuronal networks could trigger biochemical alterations leading to a temporary decrease in N-acetylaspartate (tNAA, considered a marker of neuronal integrity), while choline (a membrane component), myo-Inositol (mI, astroglia marker), and glutamate/glutamine (Glx, excitatory neurotransmitter) were postulated to increase. Previous magnetic resonance spectroscopy studies, reporting diverse findings, have used two different referencing methods - creatine ratios and tissue corrected values referenced to water - for the quantification of brain metabolites. Changes in creatine during ECT have also been reported, which may confound estimates adopting this as an internal reference. Methods: Using MR spectroscopy, we investigated 31 moderately to severely depressed patients and 19 healthy controls before, during, and after ECT or at similar time points (for controls). We tested whether biochemical alterations in tNAA, choline, mI, and Glx lend support to the disrupt, potentiate, and rewire hypothesis. We used both creatine ratios and water-scaled values for the quantification of brain metabolites to validate the results across referencing methods. Results: Levels of tNAA in the anterior cingulate cortex decreased after an ECT treatment series (average 10.6 sessions) by 6% (p = 0.007, creatine ratio) and 3% (p = 0.02, water referenced) but returned to baseline 6 months after ECT. Compared to after treatment series tNAA levels at 6-month follow-up had increased in both creatine ratio (+6%, p < 0.001) and water referenced data (+7%, p < 0.001). Findings for other brain metabolites varied and could not be validated across referencing methods. Discussion: Our findings suggest that prior research must be interpreted with care, as several referencing and processing methods have been used in the past. Yet, the results for tNAA were robust across quantification methods and concur with relevant parts of the disrupt, potentiate, and rewire model.

Anxiety, mood, and substance use disorders in adult men and women with and without attention-deficit/hyperactivity disorder: A substantive and methodological overview.

Knowledge on psychiatric comorbidity in adult ADHD is essential for prevention, detection, and treatment of these conditions. This review (1) focuses on large studies (n > 10,000; surveys, claims data, population registries) to identify (a) overall, (b) sex- and (c) age-specific patterns of comorbidity of anxiety disorders (ADs), major depressive disorder (MDD), bipolar disorder (BD) and substance use disorders (SUDs) in adults with ADHD relative to adults without ADHD; and (2) describes methodological challenges relating to establishing comorbidity in ADHD in adults as well as priorities for future research. Meta-analyses (ADHD: n = 550,748; no ADHD n = 14,546,814) yielded pooled odds ratios of 5.0(CI:3.29-7.46) for ADs, 4.5(CI:2.44-8.34) for MDD, 8.7(CI:5.47-13.89) for BD and 4.6(CI:2.72-7.80) for SUDs, indicating strong differences in adults with compared to adults without ADHD. Moderation by sex was not found: high comorbidity held for both men and women with sex-specific patterns as in the general population: higher prevalences of ADs, MDD and BD in women and a higher prevalence of SUDs in men. Insufficient data on different phases of the adult lifespan prevented conclusions on developmental changes in comorbidity. We discuss methodological challenges, knowledge gaps, and future research priorities.

Do Poor Diet and Lifestyle Behaviors Modify the Genetic Susceptibility to Impulsivity in the General Population?

The present study investigated whether an unhealthy diet and other lifestyle behaviors may modify the genetic susceptibility to impulsivity. A total of 33,047 participants (mean age = 42.1 years, 59.8% females) from the Dutch Lifelines cohort were included. Each diet index and other lifestyle behaviors were tested for their interactions on the effect on the attention-deficit/hyperactivity disorder (ADHD) polygenic risk score (PRS) on impulsivity using a linear regression model with adjustment for covariates. The ADHD PRS was significantly associated with impulsivity (B = 0.03 (95% CI: 0.02, 0.04); p = 2.61 × 10-9). A poorer diet, a higher intake of energy, and a higher intake of fat were all associated with higher impulsivity, and a high intake of energy amplified the effect of ADHD PRS on impulsivity (e.g., for the interaction term of ADHD PRS and highest tertile on intake of energy, B = 0.038 (95% CI: 0.014, 0.062); p = 0.002. The other lifestyle factors, namely short and long sleep duration, current and past smoking, higher alcohol intake, and more time spent on moderate-to-vigorous physical activity were associated with higher impulsivity, but no interaction effect was observed. In conclusion, we found that a high intake of energy exacerbated the genetic susceptibility to impulsivity. Our study helps to improve our understanding of the role of diet and genetic factors on impulsivity.

Bridging Big Data: Procedures for Combining Non-equivalent Cognitive Measures from the ENIGMA Consortium.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individual's latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences.

Labor epidural analgesia and subsequent risk of offspring autism spectrum disorder and attention-deficit/hyperactivity disorder: a cross-national cohort study of 4.5 million individuals and their siblings.

BACKGROUND: A recent study has suggested that labor epidural analgesia may be associated with increased rates of offspring autism spectrum disorder. Subsequent replication attempts have lacked sufficient power to confidently exclude the possibility of a small effect, and the causal nature of this association remains unknown. OBJECTIVE: This study aimed to investigate the extent to which exposure to labor epidural analgesia is associated with offspring autism spectrum disorder and attention-deficit/hyperactivity disorder following adjustments for unmeasured familial confounding. STUDY DESIGN: We identified 4,498,462 singletons and their parents using the Medical Birth Registers in Finland (cohorts born from 1987-2005), Norway (1999-2015), and Sweden (1987-2011) linked with population and patient registries. These cohorts were followed from birth until they either had the outcomes of interest, emigrated, died, or reached the end of the follow-up (at mean ages 13.6-16.8 years), whichever occurred first. Cox regression models were used to estimate country-specific associations between labor epidural analgesia recorded at birth and outcomes (eg, at least 1 secondary care diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder or at least 1 dispensed prescription of medication used for the treatment of attention-deficit/hyperactivity disorder). The models were adjusted for sex, birth year, birth order, and unmeasured familial confounders via sibling comparisons. Pooled estimates across all the 3 countries were estimated using inverse variance weighted fixed-effects meta-analysis models. RESULTS: A total of 4,498,462 individuals (48.7% female) were included, 1,091,846 (24.3%) of which were exposed to labor epidural analgesia. Of these, 1.2% were diagnosed with autism spectrum disorder and 4.0% with attention-deficit/hyperactivity disorder. On the population level, pooled estimates showed that labor epidural analgesia was associated with increased risk of offspring autism spectrum disorder (adjusted hazard ratio, 1.12; 95% confidence interval, 1.10-1.14, absolute risks, 1.20% vs 1.07%) and attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.20; 95% confidence interval, 1.19-1.21; absolute risks, 3.95% vs 3.32%). However, when comparing full siblings who were differentially exposed to labor epidural analgesia, the associations were fully attenuated for both conditions with narrow confidence intervals (adjusted hazard ratio [autism spectrum disorder], 0.98; 95% confidence interval, 0.93-1.03; adjusted hazard ratio attention-deficit/hyperactivity disorder, 0.99; 95% confidence interval, 0.96-1.02). CONCLUSION: In this large cross-national study, we found no support for the hypothesis that exposure to labor epidural analgesia causes either offspring autism spectrum disorder or attention-deficit/hyperactivity disorder.