Publications by authors named "Natàlia Vilor-Tejedor"

33 Publications

Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer's continuum.

Alzheimers Res Ther 2021 08 5;13(1):135. Epub 2021 Aug 5.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown.

Objective: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors.

Methods: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071).

Results: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants.

Conclusions: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum.
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http://dx.doi.org/10.1186/s13195-021-00878-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340485PMC
August 2021

Genetic association study of childhood aggression across raters, instruments, and age.

Transl Psychiatry 2021 07 30;11(1):413. Epub 2021 Jul 30.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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http://dx.doi.org/10.1038/s41398-021-01480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324785PMC
July 2021

Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile.

Alzheimers Res Ther 2021 07 27;13(1):134. Epub 2021 Jul 27.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Wellington 30, 08005, Barcelona, Spain.

Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile.

Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [F]-FDG, and [F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex.

Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2.

Conclusions: There are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials.

Trial Registration: NCT02485730.
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http://dx.doi.org/10.1186/s13195-021-00863-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314554PMC
July 2021

DNA methylation signature as a biomarker of major neuropsychiatric disorders.

J Psychiatr Res 2021 09 11;141:34-49. Epub 2021 Jun 11.

BarcelonaBeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Carrer Wellington 30, 08005, Barcelona, Spain; Center for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Spain. Electronic address:

DNA methylation is a broadly-investigated epigenetic modification that has been considered as a heritable and reversible change. Previous findings have indicated that DNA methylation regulates gene expression in the central nervous system (CNS). Also, disturbance of DNA methylation patterns has been associated with destructive consequences that lead to human brain diseases such as neuropsychiatric disorders (NPDs). In this review, we comprehensively discuss the mechanism and function of DNA methylation and its most recent associations with the pathology of NPDs-including major depressive disorder (MDD), schizophrenia (SZ), autism spectrum disorder (ASD), bipolar disorder (BD), and attention/deficit hyperactivity disorder (ADHD). We also discuss how heterogeneous findings demand further investigations. Finally, based on the recent studies we conclude that DNA methylation status may have implications in clinical diagnostics and therapeutics as a potential epigenetic biomarker of NPDs.
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http://dx.doi.org/10.1016/j.jpsychires.2021.06.013DOI Listing
September 2021

Genetic Influences on Hippocampal Subfields: An Emerging Area of Neuroscience Research.

Neurol Genet 2021 Jun 21;7(3):e591. Epub 2021 May 21.

Barcelonaβeta Brain Research Center (BBRC) (N.V.-T., J.M.G.-d-E., J.L.M., J.D.G., G.O.), Pasqual Maragall Foundation; Centre for Genomic Regulation (CRG) (N.V.-T., R.G.), the Barcelona Institute for Science and Technology, Spain; Department of Clinical Genetics (N.V.-T., T.E.E., H.H.A.), Erasmus Medical Center, Rotterdam, the Netherlands; Universitat Pompeu Fabra (N.V.-T., J.M.G.--E., J.L.M., R.G., J.D.G.), Barcelona, Spain; Department of Radiology and Nuclear Medicine (H.H.A.), Erasmus Medical Center, Rotterdam, the Netherlands; IMIM (Hospital del Mar Medical Research Institute) (J.L.M., J.D.G., G.O.), Barcelona, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES) (J.L.M., G.O.); and Centro de Investigación Biomédica en Red Bioingeniería (J.D.G.), Biomateriales y Nanomedicina, Madrid, Spain.

There is clear evidence that hippocampal subfield volumes have partly distinct genetic determinants associated with specific biological processes. The identification of genetic correlates of hippocampal subfield volumes may help to elucidate the mechanisms of neurologic diseases, as well as aging and neurodegenerative processes. However, despite the emerging interest in this area of research, the current knowledge of the genetic architecture of hippocampal subfields has not yet been consolidated. We aimed to provide a review of the current evidence from genetic studies of hippocampal subfields, highlighting current priorities and upcoming challenges. The limited number of studies investigating the influential genetic effects on hippocampal subfields, a lack of replicated results and longitudinal designs, and modest sample sizes combined with insufficient standardization of protocols are identified as the most pressing challenges in this emerging area of research.
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http://dx.doi.org/10.1212/NXG.0000000000000591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192059PMC
June 2021

Genetic Predisposition to Alzheimer's Disease Is Associated with Enlargement of Perivascular Spaces in Centrum Semiovale Region.

Genes (Basel) 2021 05 27;12(6). Epub 2021 May 27.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 08005 Barcelona, Spain.

This study investigated whether genetic factors involved in Alzheimer's disease (AD) are associated with enlargement of Perivascular Spaces (ePVS) in the brain. A total of 680 participants with T2-weighted MRI scans and genetic information were acquired from the ALFA study. ePVS in the basal ganglia (BG) and the centrum semiovale (CS) were assessed based on a validated visual rating scale. We used univariate and multivariate logistic regression models to investigate associations between ePVS in BG and CS with -rs744373, as well as genotypes. We found a significant association of the -rs744373 polymorphism in the CS subscale ( value = 0.019; OR = 2.564), suggesting that G allele carriers have an increased risk of ePVS in comparison with A allele carriers. In stratified analysis by - status (carriers vs. non-carriers), these results remained significant only for ε4 carriers ( value = 0.011; OR = 1.429). To our knowledge, the present study is the first suggesting that genetic predisposition for AD is associated with ePVS in CS. These findings provide evidence that underlying biological processes affecting AD may influence CS-ePVS.
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http://dx.doi.org/10.3390/genes12060825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226614PMC
May 2021

Amyloid-β positive individuals with subjective cognitive decline present increased CSF neurofilament light levels that relate to lower hippocampal volume.

Neurobiol Aging 2021 08 6;104:24-31. Epub 2021 Mar 6.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain; Present address: H. Lundbeck A/S, Denmark. Electronic address:

Neurofilament light chain (NfL) is an axonal protein that when measured in cerebrospinal fluid (CSF) serves as a biomarker of neurodegeneration. We aimed at investigating the association among CSF NfL, presence of Subjective Cognitive Decline (SCD) and hippocampal volume, and how CSF amyloid-β (Aβ) modifies these associations. We included 278 cognitively unimpaired participants from the Alfa+ cohort (78 SCD and 200 Controls). Linear models accounting for covariates (age, gender, and mood) were used to test the association between CSF NfL and SCD status, and between CSF NfL and bilateral hippocampal volumes. Interactions with Aβ were also explored. Individuals with SCD had higher CSF NfL and lower CSF Aβ42/40 than Controls. There was a significant interaction between SCD and CSF-Aβ42/40 levels. Stratified analyses showed a significant association between SCD and NfL only in Aβ+ individuals. Higher CSF NfL was significantly associated with lower hippocampal volume specifically in Aβ+ individuals with SCD. The presence of SCD in Aβ+ individuals may represent an early symptom in the Alzheimer's continuum related to incipient neurodegeneration.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.026DOI Listing
August 2021

Strategies to reduce sample sizes in Alzheimer's disease primary and secondary prevention trials using longitudinal amyloid PET imaging.

Alzheimers Res Ther 2021 04 19;13(1):82. Epub 2021 Apr 19.

Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.

Background: Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer's disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials.

Methods: Baseline and annualized % change in [C]PIB SUVR and DVR were computed for a global (cortical) and regional (early) composite from scans of 237 cognitively unimpaired subjects from the OASIS-3 database ( www.oasis-brains.org ). Bland-Altman and correlation analyses were used to assess the relationship between SUVR and DVR. General linear models and linear mixed effects models were used to determine effects of age, sex, and APOE-ε4 carriership on baseline and longitudinal amyloid burden. Finally, differences in statistical power of SUVR and DVR (cortical or early composite) were assessed considering three anti-amyloid trial scenarios: secondary prevention trials including subjects with (1) intermediate-to-high (Centiloid > 20.1), or (2) intermediate (20.1 < Centiloid ≤ 49.4) amyloid burden, and (3) a primary prevention trial focusing on subjects with low amyloid burden (Centiloid ≤ 20.1). Trial scenarios were set to detect 20% reduction in accumulation rates across the whole population and in APOE-ε4 carriers only.

Results: Although highly correlated to DVR (ρ = .96), cortical SUVR overestimated DVR cross-sectionally and in annual % change. In secondary prevention trials, DVR required 143 subjects per arm, compared with 176 for SUVR. Both restricting inclusion to individuals with intermediate amyloid burden levels or to APOE-ε4 carriers alone further reduced sample sizes. For primary prevention, SUVR required less subjects per arm (n = 855) compared with DVR (n = 1508) and the early composite also provided considerable sample size reductions (n = 855 to n = 509 for SUVR, n = 1508 to n = 734 for DVR).

Conclusion: Sample sizes in AD secondary prevention trials can be reduced by the acquisition of dynamic PET scans and/or by restricting inclusion to subjects with intermediate amyloid burden or to APOE-ε4 carriers only. Using a targeted early composite only leads to reductions of sample size requirements in primary prevention trials. These findings support strategies to enable smaller Proof-of-Concept Phase II clinical trials to better streamline drug development.
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http://dx.doi.org/10.1186/s13195-021-00819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056524PMC
April 2021

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

Transposable elements in brain health and disease.

Ageing Res Rev 2020 12 22;64:101153. Epub 2020 Sep 22.

CEINGE-Biotecnologie Avanzate, Naples, Italy. Electronic address:

Transposable elements (TEs) occupy a large fraction of the human genome but only a small proportion of these elements are still active today. Recent works have suggested that TEs are expressed and active in the brain, challenging the dogma that neuronal genomes are static and revealing that they are susceptible to somatic genomic alterations. These new findings have major implications for understanding the neuroplasticity of the brain, which could hypothetically have a role in behavior and cognition, and contribute to vulnerability to disease. As active TEs could induce genetic diversity and mutagenesis, their influences on human brain development and diseases are of great interest. In this review, we will focus on the active TEs in the human genome and discuss in detail their impacts on human brain development. Furthermore, the association between TEs and brain-related diseases is discussed.
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http://dx.doi.org/10.1016/j.arr.2020.101153DOI Listing
December 2020

Polygenic risk for ADHD and ASD and their relation with cognitive measures in school children.

Psychol Med 2020 Sep 14:1-9. Epub 2020 Sep 14.

Barcelona Research Institute for Global Health (ISGlobal), Barcelona, Spain.

Background: Attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are child-onset neurodevelopmental disorders frequently accompanied by cognitive difficulties. In the current study, we aim to examine the genetic overlap between ADHD and ASD and cognitive measures of working memory (WM) and attention performance among schoolchildren using a polygenic risk approach.

Methods: A total of 1667 children from a population-based cohort aged 7-11 years with data available on genetics and cognition were included in the analyses. Polygenic risk scores (PRS) were calculated for ADHD and ASD using results from the largest GWAS to date (N = 55 374 and N = 46 351, respectively). The cognitive outcomes included verbal and numerical WM and the standard error of hit reaction time (HRTSE) as a measure of attention performance. These outcomes were repeatedly assessed over 1-year period using computerized version of the Attention Network Test and n-back task. Associations were estimated using linear mixed-effects models.

Results: Higher polygenic risk for ADHD was associated with lower WM performance at baseline time but not over time. These findings remained significant after adjusting by multiple testing and excluding individuals with an ADHD diagnosis but were limited to boys. PRS for ASD was only nominally associated with an increased improvement on verbal WM over time, although this association did not survive multiple testing correction. No associations were observed for HRTSE.

Conclusions: Common genetic variants related to ADHD may contribute to worse WM performance among schoolchildren from the general population but not to the subsequent cognitive-developmental trajectory assessed over 1-year period.
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http://dx.doi.org/10.1017/S0033291720003189DOI Listing
September 2020

Effect of BDNF Val66Met on hippocampal subfields volumes and compensatory interaction with APOE-ε4 in middle-age cognitively unimpaired individuals from the ALFA study.

Brain Struct Funct 2020 Nov 17;225(8):2331-2345. Epub 2020 Aug 17.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: Current evidence supports the involvement of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, and the ε4 allele of APOE gene in hippocampal-dependent functions. Previous studies on the association of Val66Met with whole hippocampal volume included patients of a variety of disorders. However, it remains to be elucidated whether there is an impact of BDNF Val66Met polymorphism on the volumes of the hippocampal subfield volumes (HSv) in cognitively unimpaired (CU) individuals, and the interactive effect with the APOE-ε4 status.

Methods: BDNF Val66Met and APOE genotypes were determined in a sample of 430 CU late/middle-aged participants from the ALFA study (ALzheimer and FAmilies). Participants underwent a brain 3D-T1-weighted MRI scan, and volumes of the HSv were determined using Freesurfer (v6.0). The effects of the BDNF Val66Met genotype on the HSv were assessed using general linear models corrected by age, gender, education, number of APOE-ε4 alleles and total intracranial volume. We also investigated whether the association between APOE-ε4 allele and HSv were modified by BDNF Val66Met genotypes.

Results: BDNF Val66Met carriers showed larger bilateral volumes of the subiculum subfield. In addition, HSv reductions associated with APOE-ε4 allele were significantly moderated by BDNF Val66Met status. BDNF Met carriers who were also APOE-ε4 homozygous showed patterns of higher HSv than BDNF Val carriers.

Conclusion: To our knowledge, the present study is the first to show that carrying the BDNF Val66Met polymorphisms partially compensates the decreased on HSv associated with APOE-ε4 in middle-age cognitively unimpaired individuals.
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http://dx.doi.org/10.1007/s00429-020-02125-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544723PMC
November 2020

Aging-Dependent Genetic Effects Associated to ADHD Predict Longitudinal Changes of Ventricular Volumes in Adulthood.

Front Psychiatry 2020 29;11:574. Epub 2020 Jun 29.

Universitat Pompeu Fabra (UPF), Barcelona, Spain.

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood-onset disorder that can persist into adult life. Most genetic studies have focused on investigating biological mechanisms of ADHD during childhood. However, little is known about whether genetic variants associated with ADHD influence structural brain changes throughout adulthood.

Methods: Participant of the study were drawn from a population-based sample of 3,220 healthy individuals drawn from the Rotterdam Study, with at least two magnetic resonance imaging (MRI)-scans (8,468 scans) obtained every 3-4 years. We investigate associations of genetic single nucleotide polymorphisms (SNPs) that have previously been identified in genome-wide association studies for ADHD, and trajectories of global and subcortical brain structures in an adult population (aged 50 years and older), acquired through MRI. We also evaluated the existence of age-dependent effects of these genetic variants on trajectories of brain structures. These analyses were reproduced among individuals 70 years of age or older to further explore aging-dependent mechanisms. We additionally tested baseline associations using the first MRI-scan of the 3,220 individuals.

Results: We observed significant age-dependent effects on the rs212178 in trajectories of ventricular size (lateral ventricles, P= 4E-05; inferior lateral ventricles, P=3.8E-03; third ventricle, P=2.5E-03; fourth ventricle, P=5.5E-03). Specifically, carriers of the G allele, which was reported as protective for ADHD, had a smaller increase of ventricular size compared with homozygotes for the A allele in elder stages. Post hoc analysis on the subset of individuals older than 70 years of age reinforced these results (lateral ventricles, P=7.3E-05). In addition, the rs4916723, and the rs281324 displayed nominal significant age-dependent effects in trajectories of the amygdala volume (P=1.4E-03), and caudate volume (P=1.8E-03), respectively.

Conclusions: To the best of our knowledge, this is the first study suggesting the involvement of protective genetic variants for ADHD on prevention of brain atrophy during adulthood.
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http://dx.doi.org/10.3389/fpsyt.2020.00574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344235PMC
June 2020

Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum.

Alzheimers Dement 2020 10 23;16(10):1358-1371. Epub 2020 Jun 23.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Introduction: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood.

Methods: We used NeuroToolKit and Elecsys immunoassays to measure cerebrospinal fluid (CSF) amyloid-β (Aβ)42, Aβ40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum.

Results: CSF t-tau, p-tau, and neurogranin increase throughout aging only in Aβ-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p-tau and p-tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers.

Discussion: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum.
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http://dx.doi.org/10.1002/alz.12131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586814PMC
October 2020

Effects of prenatal exposure to particulate matter air pollution on corpus callosum and behavioral problems in children.

Environ Res 2019 11 7;178:108734. Epub 2019 Sep 7.

ISGLOBAL, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Pompeu Fabra University, Barcelona, Catalonia, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Institut Hospital del Mar d'Investigacions Mèdiques-Parc de Salut Mar, Barcelona, Catalonia, Spain.

Objective: Air pollution (AP) may affect neurodevelopment, but studies about the effects of AP on the growing human brain are still scarce. We aimed to investigate the effects of prenatal exposure to AP on lateral ventricles (LV) and corpus callosum (CC) volumes in children and to determine whether the induced brain changes are associated with behavioral problems.

Methods: Among the children recruited through a set of representative schools of the city of Barcelona, (Spain) in the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) study, 186 typically developing participants aged 8-12 years underwent brain MRI on the same 1.5 T MR unit over a 1.5-year period (October 2012-April 2014). Brain volumes were derived from structural MRI scans using automated tissue segmentation. Behavioral problems were assessed using the Strengths and Difficulties Questionnaire (SDQ) and the criteria of the Attention Deficit Hyperactivity Disorder DSM-IV list. Prenatal fine particle (PM) levels were retrospectively estimated at the mothers' residential addresses during pregnancy with land use regression (LUR) models. To determine whether brain structures might be affected by prenatal PM exposure, linear regression models were run and adjusted for age, sex, intracranial volume (ICV), maternal education, home socioeconomic vulnerability index, birthweight and mothers' smoking status during pregnancy. To test for associations between brain changes and behavioral outcomes, negative binomial regressions were performed and adjusted for age, sex, ICV.

Results: Prenatal PM levels ranged from 11.8 to 39.5 μg/m during the third trimester of pregnancy. An interquartile range increase in PM level (7 μg/m) was significantly linked to a decrease in the body CC volume (mm) (β = -53.7, 95%CI [-92.0, -15.5] corresponding to a 5% decrease of the mean body CC volume) independently of ICV, age, sex, maternal education, socioeconomic vulnerability index at home, birthweight and mothers' smoking status during the third trimester of pregnancy. A 50 mm decrease in the body CC was associated with a significant higher hyperactivity subscore (Rate Ratio (RR) = 1.09, 95%CI [1.01, 1.17) independently of age, sex and ICV. The statistical significance of these results did not survive to False Discovery Rate correction for multiple comparisons.

Conclusions: Prenatal exposure to PM may be associated with CC volume decrease in children. The consequences might be an increase in behavioral problems.
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http://dx.doi.org/10.1016/j.envres.2019.108734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892268PMC
November 2019

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Hum Mol Genet 2019 10;28(19):3327-3338

Unidad de Investigacion Medica en Bioquımica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.
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http://dx.doi.org/10.1093/hmg/ddz161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859434PMC
October 2019

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
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http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019

Prenatal Omega-6:Omega-3 Ratio and Attention Deficit and Hyperactivity Disorder Symptoms.

J Pediatr 2019 06 28;209:204-211.e4. Epub 2019 Mar 28.

Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Biomedical Research Networking Centres Epidemiology and Public Health (CIBERESP), Madrid, Spain; Hospital del Mar Medical Research Institute, Barcelona, Spain.

Objective: To evaluate whether higher omega-6:omega-3 (n-6:n-3) long-chain polyunsaturated fatty acid ratio in cord plasma is associated with more symptoms of attention deficit and hyperactivity disorder (ADHD) at 4 and 7 years of age.

Study Design: This study was based on a population-based birth cohort in Spain. N-6 arachidonic acid and n-3 eicosapentaenoic and docosahexaenoic acid concentrations were measured in cord plasma. At 4 years old, ADHD symptoms were reported by teachers through the ADHD Diagnostic and Statistical Manual of Mental Disorders, 4th ed checklist (n = 580). At 7 years old, ADHD symptoms were reported by parents through the Conners' Rating Scale-Revised (short form; n = 642). The ADHD variable was treated as continuous (score) and as dichotomous (symptom diagnostic criteria). Child and family general characteristics were prospectively collected through questionnaires. We applied pooled zero-inflated negative binomial and logistic regressions adjusted for covariates.

Results: A higher omega-6:omega-3 long-chain polyunsaturated fatty acid ratio in cord plasma was associated with a higher ADHD index (incidence rate ratio, 1.13; 95% CI, 1.03, 1.23) at 7 years old. The association was not observed at 4 years old (incidence rate ratio, 1.04; 95% CI, 0.92-1.18). No associations were found using ADHD symptom diagnostic criteria.

Conclusions: High prenatal omega-6:omega-3 long-chain polyunsaturated fatty acid ratio preceded the appearance of subclinical ADHD symptoms during mid-childhood. Our findings suggest that maternal diet during pregnancy may modulate the risk to develop long-term ADHD symptoms in the offspring.
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http://dx.doi.org/10.1016/j.jpeds.2019.02.022DOI Listing
June 2019

Independent Multiple Factor Association Analysis for Multiblock Data in Imaging Genetics.

Neuroinformatics 2019 10;17(4):583-592

Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain.

Multivariate methods have the potential to better capture complex relationships that may exist between different biological levels. Multiple Factor Analysis (MFA) is one of the most popular methods to obtain factor scores and measures of discrepancy between data sets. However, singular value decomposition in MFA is based on PCA, which is adequate only if the data is normally distributed, linear or stationary. In addition, including strongly correlated variables can overemphasize the contribution of the estimated components. In this work, we introduced a novel method referred as Independent Multifactorial Analysis (ICA-MFA) to derive relevant features from multiscale data. This method is an extended implementation of MFA, where the component value decomposition is based on Independent Component Analysis. In addition, ICA-MFA incorporates a predictive step based on an Independent Component Regression. We evaluated and compared the performance of ICA-MFA with both, the MFA method and traditional univariate analyses, in a simulation study. We showed how ICA-MFA explained up to 10-fold more variance than MFA and univariate methods. We applied the proposed algorithm in a study of 4057 individuals belonging to the population-based Rotterdam Study with available genetic and neuroimaging data, as well as information about executive cognitive functioning. Specifically, we used ICA-MFA to detect relevant genetic features related to structural brain regions, which in turn were involved, in the mechanisms of executive cognitive function. The proposed strategy makes it possible to determine the degree to which the whole set of genetic and/or neuroimaging markers contribute to the variability of the symptomatology jointly, rather than individually. While univariate results and MFA combinations only explained a limited proportion of variance (less than 2%), our method increased the explained variance (10%) and allowed the identification of significant components that maximize the variance explained in the model. The potential application of the ICA-MFA algorithm constitutes an important aspect of integrating multivariate multiscale data, specifically in the field of Neurogenetics.
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http://dx.doi.org/10.1007/s12021-019-09416-zDOI Listing
October 2019

Sparse multiple factor analysis to integrate genetic data, neuroimaging features, and attention-deficit/hyperactivity disorder domains.

Int J Methods Psychiatr Res 2018 09 14;27(3):e1738. Epub 2018 Aug 14.

ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.

Objectives: We proposed the application of a multivariate cross-sectional framework based on a combination of a variable selection method and a multiple factor analysis (MFA) in order to identify complex meaningful biological signals related to attention-deficit/hyperactivity disorder (ADHD) symptoms and hyperactivity/inattention domains.

Methods: The study included 135 children from the general population with genomic and neuroimaging data. ADHD symptoms were assessed using a questionnaire based on ADHD-DSM-IV criteria. In all analyses, the raw sum scores of the hyperactivity and inattention domains and total ADHD were used. The analytical framework comprised two steps. First, zero-inflated negative binomial linear model via penalized maximum likelihood (LASSO-ZINB) was performed. Second, the most predictive features obtained with LASSO-ZINB were used as input for the MFA.

Results: We observed significant relationships between ADHD symptoms and hyperactivity and inattention domains with white matter, gray matter regions, and cerebellum, as well as with loci within chromosome 1.

Conclusions: Multivariate methods can be used to advance the neurobiological characterization of complex diseases, improving the statistical power with respect to univariate methods, allowing the identification of meaningful biological signals in Imaging Genetic studies.
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http://dx.doi.org/10.1002/mpr.1738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877273PMC
September 2018

Traffic-Related Air Pollution, ε4 Status, and Neurodevelopmental Outcomes among School Children Enrolled in the BREATHE Project (Catalonia, Spain).

Environ Health Perspect 2018 08 2;126(8):087001. Epub 2018 Aug 2.

ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain

Background: Traffic-related air pollution is emerging as a risk factor for Alzheimer's disease (AD) and impaired brain development. Individual differences in vulnerability to air pollution may involve the ε4 allele of () gene, the primary genetic risk factor for AD.

Objective: We analyzed whether the association between traffic air pollution and neurodevelopmental outcomes is modified by ε4 status in children.

Methods: Data on parent-reported behavior problems (total difficulties scores, Strengths and Difficulties Questionnaire), teacher-reported attention-deficit hyperactivity disorder (ADHD) symptom scores, cognitive performance trajectories (computerized tests of inattentiveness and working memory repeated 2-4 times during January 2012-March 2013), and genotypes were obtained for 1,667 children age 7-11 y attending 39 schools in or near Barcelona. Basal ganglia volume (putamen, caudate, and globus pallidum) was measured in 163 of the children by MRI (October 2012-April 2014.) Average annual outdoor polycyclic aromatic hydrocarbons (PAHs), elemental carbon (EC), and nitrogen dioxide (NO) concentrations were estimated based on measurements at each school (two 1-wk campaigns conducted 6 months apart in 2012).

Results: ε4 allele carriers had significantly higher behavior problem scores than noncarriers, and adverse associations with PAHs and NO were stronger or limited to ε4 carriers for behavior problem scores (-interaction 0.03 and 0.04), caudate volume (-interaction 0.04 and 0.03), and inattentiveness trajectories (-interaction 0.15 and 0.08, respectively). Patterns of associations with the same outcomes were similar for EC.

Conclusion: PAHs, EC, and NO were associated with higher behavior problem scores, smaller reductions in inattentiveness over time, and smaller caudate volume in ε4 allele carriers in our study population, and corresponding associations were weak or absent among ε4 noncarriers. These findings support a potential role of in biological mechanisms that may contribute to associations between air pollution and neurobehavioral outcomes in children. https://doi.org/10.1289/EHP2246.
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http://dx.doi.org/10.1289/EHP2246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108838PMC
August 2018

Strategies for integrated analysis in imaging genetics studies.

Neurosci Biobehav Rev 2018 10 23;93:57-70. Epub 2018 Jun 23.

Barcelona Research Institute for Global Health (ISGlobal), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. Electronic address:

Imaging Genetics (IG) integrates neuroimaging and genomic data from the same individual, deepening our knowledge of the biological mechanisms behind neurodevelopmental domains and neurological disorders. Although the literature on IG has exponentially grown over the past years, the majority of studies have mainly analyzed associations between candidate brain regions and individual genetic variants. However, this strategy is not designed to deal with the complexity of neurobiological mechanisms underlying behavioral and neurodevelopmental domains. Moreover, larger sample sizes and increased multidimensionality of this type of data represents a challenge for standardizing modeling procedures in IG research. This review provides a systematic update of the methods and strategies currently used in IG studies, and serves as an analytical framework for researchers working in this field. To complement the functionalities of the Neuroconductor framework, we also describe existing R packages that implement these methodologies. In addition, we present an overview of how these methodological approaches are applied in integrating neuroimaging and genetic data.
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http://dx.doi.org/10.1016/j.neubiorev.2018.06.013DOI Listing
October 2018

Efficient and Powerful Method for Combining P-Values in Genome-Wide Association Studies.

IEEE/ACM Trans Comput Biol Bioinform 2016 11 22;13(6):1100-1106. Epub 2015 Dec 22.

Department of Systems Biology, Bioinformatics and Medical Statistics Group, Universitat de Vic-Universitat Central de Catalunya, C. Sagrada Familia 7, Vic, Spain.

The goal of Genome-wide Association Studies (GWAS) is the identification of genetic variants, usually single nucleotide polymorphisms (SNPs), that are associated with disease risk. However, SNPs detected so far with GWAS for most common diseases only explain a small proportion of their total heritability. Gene set analysis (GSA) has been proposed as an alternative to single-SNP analysis with the aim of improving the power of genetic association studies. Nevertheless, most GSA methods rely on expensive computational procedures that make unfeasible their implementation in GWAS. We propose a new GSA method, referred as globalEVT, which uses the extreme value theory to derive gene-level p-values. GlobalEVT reduces dramatically the computational requirements compared to other GSA approaches. In addition, this new approach improves the power by allowing different inheritance models for each genetic variant as illustrated in the simulation study performed and allows the existence of correlation between the SNPs. Real data analysis of an Attention-deficit/hyperactivity disorder (ADHD) study illustrates the importance of using GSA approaches for exploring new susceptibility genes. Specifically, the globalEVT method is able to detect genes related to Cyclophilin A like domain proteins which is known to play an important role in the mechanisms of ADHD development.
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http://dx.doi.org/10.1109/TCBB.2015.2509977DOI Listing
November 2016

Imaging genetics in attention-deficit/hyperactivity disorder and related neurodevelopmental domains: state of the art.

Brain Imaging Behav 2017 Dec;11(6):1922-1931

ISGLOBAL, Centre for Research in Environmental Epidemiology, Barcelona, Spain.

Joint analysis of genetic and neuroimaging data, known as Imaging Genetics (IG), offers an opportunity to deepen our knowledge of the biological mechanisms of neurodevelopmental domains. There has been exponential growth in the literature on IG studies, which challenges the standardization of analysis methods in this field. In this review we give a complete up-to-date account of IG studies on attention deficit hyperactivity disorder (ADHD) and related neurodevelopmental domains, which serves as a reference catalog for researchers working on this neurological disorder. We searched MEDLINE/Pubmed and identified 37 articles on IG of ADHD that met our eligibility criteria. We carefully cataloged these articles according to imaging technique, genes and brain region, and summarized the main results and characteristics of each study. We found that IG studies on ADHD generally focus on dopaminergic genes and the structure of basal ganglia using structural Magnetic Resonance Imaging (MRI). We found little research involving multiple genetic factors and brain regions because of the scarce use of multivariate strategies in data analysis. IG of ADHD and related neurodevelopmental domains is still in its early stages, and a lack of replicated findings is one of the most pressing challenges in the field.
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http://dx.doi.org/10.1007/s11682-016-9663-xDOI Listing
December 2017

Genome-wide associations for birth weight and correlations with adult disease.

Nature 2016 10 28;538(7624):248-252. Epub 2016 Sep 28.

Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (R = -0.22, P = 5.5 × 10), T2D (R = -0.27, P = 1.1 × 10) and coronary artery disease (R = -0.30, P = 6.5 × 10). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
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http://dx.doi.org/10.1038/nature19806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164934PMC
October 2016

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts.

J Am Acad Child Adolesc Psychiatry 2016 10 5;55(10):896-905.e6. Epub 2016 Aug 5.

Dr. Middeldorp is with Biological Psychology, Neuroscience Campus Amsterdam, VU University Amsterdam, and GGZinGeest/ VU University Medical Center, Amsterdam. Ms. Hammerschlag is with the Generation R Study Group, Erasmus MC Rotterdam, the Netherlands, and Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam. Mr. Ouwens and Dr. Groen-Blokhuis are with Biological Psychology, VU University Amsterdam, and the EMGO+ Institute for Health and Care Research, VU University Medical Center. Dr. St. Pourcain is with MRC Integrative Epidemiology Unit (MRC IEU), University of Bristol, UK, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands, and School of Experimental Psychology, University of Bristol. Dr. Greven is with Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Karakter, Child and Adolescent Psychiatry University Center, Radboud University Nijmegen, and MRC Social Genetic and Developmental Psychiatry Centre, King's College London. Dr. Pappa is with Generation R Study Group, and Pedagogical and Education Science, Erasmus University Rotterdam, The Netherlands. Drs. Tiesler and Thiering are with Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany and the Division of Metabolic and Nutritional Medicine, Munich, and Dr. von Hauner Children's Hospital, University of Munich Medical Center, Germany. Mr. Ang, Ms. Wang, and Dr. Pennell are with School of Women's and Infants' Health, University of Western Australia, Perth. Dr. Nolte is with University of Groningen, University Medical Center Groningen, The Netherlands. Ms. Vilor-Tejedor is with Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Universitat Pompeu Fabra (UPF), Barcelona, and CIBER Epidemiology and Public Health (CIBERESP), Madrid. Mr. Bacelis is with Gothenburg University, Sweden. Drs. Ebejer, Martin, and Medland are with QIMR Berghofer Medical Research Institute, Brisbane, Australia. Drs. Zhao and Nyholt are with Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia. Drs. Davies and Ehli are with Avera Institute for Human Genetics, SD. Drs. Evans, Kemp, and Ring are with MRC IEU, School of Social and Community Medicine, and School of Social and Community Medicine, University of Bristol, and Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane. Ms. Fedko is with Biological Psychology, VU University Amsterdam. Dr. Guxens is with CREAL, UPF, CIBERESP, and Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children´s Hospital, The Netherlands. Dr. Hottenga is with Biological Psychology, VU University, and EMGO+ Institute for Health and Care Research, VU University Medical Center. Dr. Hudziak is with Vermont Center for Children, Youth and Families and College of Medicine, University of Vermont, Burlington, and Child and Adolescent Psychiatry, Erasmus Medical Center. Drs. Jugessur, Myhre, and Stoltenberg are with the Norwegian Institute of Public Health, Oslo. Ms. Krapohl and Drs. Trzaskowski and Plomin are with MRC Social, Genetic and Developmental Psychiatry Centre, King's College London. Mr. Murcia is with CIBERESP, and FISABIO-Universitat Jaume I-Universitat de València Joint Research Unit of Epidemiology and Environmental Health, Valencia, Spain. Drs. Ormel and Hartman are with the Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), University Medical Center Groningen. Drs. Standl and Heinrich are with Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. Drs. Stergiakouli and Timpson are with MRC IEU; Dr. Timpson is also with School of Social and Community Medicine, University of Bristol. Dr. van der Most is with University of Groningen and University Medical Center Groningen. Dr. Neale is with Program in Medical and Population Genetics and Stanley Center for Psychiatric Genetics, Broad Institute of Massachusetts Institute of Technology, Boston, Analytic and Translation Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, and Harvard University, Cambridge, MA. Dr. Jacobsson is with Obstetrics and Gynecology, Gothenburg University, and the Norwegian Institute of Public Health. Dr. Sunyer is with CREAL, IMIM (Hospital del Mar Medical Research Institute), Barcelona, UPF, and CIBERESP. Dr. Whitehouse is with Telethon Kids Institute, University of Western Australia, Perth. Dr. Davey Smith is with MRC IEU, and School of Social and Community Medicine. Dr. Tiemeier is with Epidemiology, Child and Adolescent Psychiatry, and Psychiatry, Erasmus Medical Center. Dr. Posthuma is with the Generation R Study Group, Erasmus MC Rotterdam, the Netherlands, Child and Adolescent Psychiatry, Erasmus Medical Center, Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, and Clinical Genetics, VU University Medical Center. Dr. Boomsma is with Biological Psychology, VU University, Neuroscience Campus Amsterdam, VU University, and EMGO+ Institute for Health and Care Research, VU University Medical Center.

Objective: The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis.

Method: Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated.

Results: SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10(-6) and 2.66 × 10(-6)). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96.

Conclusion: The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068552PMC
http://dx.doi.org/10.1016/j.jaac.2016.05.025DOI Listing
October 2016

A Genome-Wide Association Study of Attention Function in a Population-Based Sample of Children.

PLoS One 2016;11(9):e0163048. Epub 2016 Sep 22.

ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.

Background: Attention function filters and selects behaviorally relevant information. This capacity is impaired in some psychiatric disorders and has been proposed as an endophenotype for Attention-Deficit/Hyperactivity Disorder; however, its genetic basis remains largely unknown. This study aimed to identify single nucleotide polymorphism (SNPs) associated with attention function.

Materials And Methods: The discovery sample included 1655 children (7-12 years) and the replication sample included 546 children (5-8 years). Five attention outcomes were assessed using the computerized Attentional Network Test (ANT): alerting, orienting, executive attention, Hit Reaction time (HRT) and the standard error of HRT (HRTSE). A Genome-wide Association Study was conducted for each outcome. Gene set enrichment analyses were performed to detect biological pathways associated with attention outcomes. Additional neuroimaging analyses were conducted to test neural effects of detected SNPs of interest.

Results: Thirteen loci showed suggestive evidence of association with attention function (P<10-5) in the discovery sample. One of them, the rs4321351 located in the PID1 gene, was nominally significant in the replication sample although it did not survive multiple testing correction. Neuroimaging analysis revealed a significant association between this SNP and brain structure and function involving the frontal-basal ganglia circuits. The mTOR signaling and Alzheimer disease-amyloid secretase pathways were significantly enriched for alerting, orienting and HRT respectively (FDR<5%).

Conclusion: These results suggest for the first time the involvement of the PID1 gene, mTOR signaling and Alzheimer disease-amyloid secretase pathways, in attention function during childhood. These genes and pathways have been proposed to play a role in neuronal plasticity, memory and neurodegenerative disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033492PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163048PLOS
September 2016

Heritability and Genome-Wide Association Analyses of Sleep Duration in Children: The EAGLE Consortium.

Sleep 2016 Oct 1;39(10):1859-1869. Epub 2016 Oct 1.

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

Study Objectives: Low or excessive sleep duration has been associated with multiple outcomes, but the biology behind these associations remains elusive. Specifically, genetic studies in children are scarce. In this study, we aimed to: (1) estimate the proportion of genetic variance of sleep duration in children attributed to common single nucleotide polymorphisms (SNPs), (2) identify novel SNPs associated with sleep duration in children, and (3) investigate the genetic overlap of sleep duration in children and related metabolic and psychiatric traits.

Methods: We performed a population-based molecular genetic study, using data form the EArly Genetics and Life course Epidemiology (EAGLE) Consortium. 10,554 children of European ancestry were included in the discovery, and 1,250 children in the replication phase.

Results: We found evidence of significant but modest SNP heritability of sleep duration in children (SNP 0.14, 95% CI [0.05, 0.23]) using the LD score regression method. A novel region at chromosome 11q13.4 (top SNP: rs74506765, P = 2.27e-08) was associated with sleep duration in children, but this was not replicated in independent studies. Nominally significant genetic overlap was only found ( = 0.23, P = 0.05) between sleep duration in children and type 2 diabetes in adults, supporting the hypothesis of a common pathogenic mechanism.

Conclusions: The significant SNP heritability of sleep duration in children and the suggestive genetic overlap with type 2 diabetes support the search for genetic mechanisms linking sleep duration in children to multiple outcomes in health and disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020368PMC
http://dx.doi.org/10.5665/sleep.6170DOI Listing
October 2016

A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways.

Hum Mol Genet 2016 09 23;25(18):4127-4142. Epub 2016 Aug 23.

Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.
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http://dx.doi.org/10.1093/hmg/ddw264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291237PMC
September 2016

Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

Hum Mol Genet 2016 Jan 24;25(2):389-403. Epub 2015 Nov 24.

School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
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http://dx.doi.org/10.1093/hmg/ddv472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854022PMC
January 2016
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