Publications by authors named "Manon Bernard"

23 Publications

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Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 Sep 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
September 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 03 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

JAMA Psychiatry 2020 04;77(4):420-430

Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam, Amsterdam, the Netherlands.

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.

Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.

Design, Setting, And Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.

Main Outcomes And Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.

Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.

Conclusions And Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.3779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822096PMC
April 2020

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

A genome-wide association study identifies genetic loci associated with specific lobar brain volumes.

Commun Biol 2019 2;2:285. Epub 2019 Aug 2.

17Department of Biomedical Data Sciences, Statistical Genetics, Leiden University Medical Center, Leiden, 2333ZA the Netherlands.

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications ( and ), or close to genes causing Mendelian brain-related diseases ( and ). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.
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http://dx.doi.org/10.1038/s42003-019-0537-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677735PMC
April 2020

Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Mol Psychiatry 2020 Mar;25(3):692-695

Department of Psychiatry and Mental Health, Anzio Road, 7925, Cape Town, South Africa.

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.
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http://dx.doi.org/10.1038/s41380-019-0358-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608381PMC
March 2020

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Mol Psychiatry 2020 03 3;25(3):584-602. Epub 2018 Oct 3.

Department of Psychiatry and Mental Health, Anzio Road, 7925, Cape Town, South Africa.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10, 1.7 × 10, 3.5 × 10 and 1.0 × 10, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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http://dx.doi.org/10.1038/s41380-018-0118-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042770PMC
March 2020

Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume.

Nat Commun 2018 09 26;9(1):3945. Epub 2018 Sep 26.

Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald 17475, Germany.

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 × 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.
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http://dx.doi.org/10.1038/s41467-018-06234-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158214PMC
September 2018

Genome-wide association meta-analysis of age at first cannabis use.

Addiction 2018 11 19;113(11):2073-2086. Epub 2018 Aug 19.

Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia.

Background And Aims: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants.

Methods: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals.

Results: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant.

Conclusion: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.
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http://dx.doi.org/10.1111/add.14368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087375PMC
November 2018

Novel genetic loci associated with hippocampal volume.

Nat Commun 2017 01 18;8:13624. Epub 2017 Jan 18.

Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA.

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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http://dx.doi.org/10.1038/ncomms13624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253632PMC
January 2017

Novel genetic loci underlying human intracranial volume identified through genome-wide association.

Nat Neurosci 2016 12 3;19(12):1569-1582. Epub 2016 Oct 3.

Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht, the Netherlands.

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
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http://dx.doi.org/10.1038/nn.4398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227112PMC
December 2016

Cohort Profile: The Saguenay Youth Study (SYS).

Int J Epidemiol 2017 04;46(2):e19

Department of Human Sciences, Université du Québec à Chicoutimi, Chicoutimi, QC, Canada.

The Saguenay Youth Study (SYS) is a two-generational study of adolescents and their parents (n = 1029 adolescents and 962 parents) aimed at investigating the aetiology, early stages and trans-generational trajectories of common cardiometabolic and brain diseases. The ultimate goal of this study is to identify effective means for increasing healthy life expectancy. The cohort was recruited from the genetic founder population of the Saguenay Lac St Jean region of Quebec, Canada. The participants underwent extensive (15-h) phenotyping, including an hour-long recording of beat-by-beat blood pressure, magnetic resonance imaging of the brain and abdomen, and serum lipidomic profiling with LC-ESI-MS. All participants have been genome-wide genotyped (with ∼ 8 M imputed single nucleotide polymorphisms) and a subset of them (144 adolescents and their 288 parents) has been genome-wide epityped (whole blood DNA, Infinium HumanMethylation450K BeadChip). These assessments are complemented by a detailed evaluation of each participant in a number of domains, including cognition, mental health and substance use, diet, physical activity and sleep, and family environment. The data collection took place during 2003-12 in adolescents (full) and their parents (partial), and during 2012-15 in parents (full). All data are available upon request.
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http://dx.doi.org/10.1093/ije/dyw023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837575PMC
April 2017

Layered genetic control of DNA methylation and gene expression: a locus of multiple sclerosis in healthy individuals.

Hum Mol Genet 2015 Oct 28;24(20):5733-45. Epub 2015 Jul 28.

The Hospital for Sick Children, University of Toronto, Toronto, Canada, Department of Physiology, Department of Nutritional Sciences,

DNA methylation may contribute to the etiology of complex genetic disorders through its impact on genome integrity and gene expression; it is modulated by DNA-sequence variants, named methylation quantitative trait loci (meQTLs). Most meQTLs influence methylation of a few CpG dinucleotides within short genomic regions (<3 kb). Here, we identified a layered genetic control of DNA methylation at numerous CpGs across a long 300 kb genomic region. This control involved a single long-range meQTL and multiple local meQTLs. The long-range meQTL explained up to 75% of variance in methylation of CpGs located over extended areas of the 300 kb region. The meQTL was identified in four samples (P = 2.8 × 10(-17), 3.1 × 10(-31), 4.0 × 10(-71) and 5.2 × 10(-199)), comprising a total of 2796 individuals. The long-range meQTL was strongly associated not only with DNA methylation but also with mRNA expression of several genes within the 300 kb region (P = 7.1 × 10(-18)-1.0 × 10(-123)). The associations of the meQTL with gene expression became attenuated when adjusted for DNA methylation (causal inference test: P = 2.4 × 10(-13)-7.1 × 10(-20)), indicating coordinated regulation of DNA methylation and gene expression. Further, the long-range meQTL was found to be in linkage disequilibrium with the most replicated locus of multiple sclerosis, a disease affecting primarily the brain white matter. In middle-aged adults free of the disease, we observed that the risk allele was associated with subtle structural properties of the brain white matter found in multiple sclerosis (P = 0.02). In summary, we identified a long-range meQTL that controls methylation and expression of several genes and may be involved in increasing brain vulnerability to multiple sclerosis.
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http://dx.doi.org/10.1093/hmg/ddv294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581603PMC
October 2015

CYP17A1 and Blood Pressure Reactivity to Stress in Adolescence.

Int J Hypertens 2015 26;2015:734586. Epub 2015 Jan 26.

The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada M5G 1X8.

Adolescents who exhibit exaggerated blood pressure (BP) reactivity to physical and mental challenges are at increased risk of developing hypertension in adulthood. BP at rest and in response to challenges is higher in males than females, beginning in early adolescence. CYP17A1 is one of the well-established gene loci of adult hypertension. Here, we investigated whether this gene locus is associated with elevated BP at rest and in response to physical (active standing) and mental (math stress) challenges in adolescence. We studied 496 male and 532 female adolescents (age 12-18 years) who were recruited from a genetic founder population. Our results showed that the variant of CYP17A1 rs10786718 was associated with enhanced BP reactivity to the mental but not physical challenge and in males but not females. In males, BP increase in response to math stress was higher in major versus minor allele homozygotes by 7.6 mm Hg (P = 8.3 × 10(-6)). Resting BP was not associated with the CYP17A1 variant in either sex. These results suggest that, in adolescent males but not females, CYP17A1 enhances BP reactivity to mental stress. Whether this effect contributes to the higher prevalence of hypertension in males than females later in life remains to be determined.
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http://dx.doi.org/10.1155/2015/734586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321855PMC
February 2015

Common genetic variants influence human subcortical brain structures.

Nature 2015 Apr 21;520(7546):224-9. Epub 2015 Jan 21.

1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
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http://dx.doi.org/10.1038/nature14101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393366PMC
April 2015

FTO, obesity and the adolescent brain.

Hum Mol Genet 2013 Mar 30;22(5):1050-8. Epub 2012 Nov 30.

The Hospital for Sick Children, University of Toronto, Toronto, Canada.

Genetic variations in fat mass- and obesity (FTO)-associated gene, a well-replicated gene locus of obesity, appear to be associated also with reduced regional brain volumes in elderly. Here, we examined whether FTO is associated with total brain volume in adolescence, thus exploring possible developmental effects of FTO. We studied a population-based sample of 598 adolescents recruited from the French Canadian founder population in whom we measured brain volume by magnetic resonance imaging. Total fat mass was assessed with bioimpedance and body mass index was determined with anthropometry. Genotype-phenotype associations were tested with Merlin under an additive model. We found that the G allele of FTO (rs9930333) was associated with higher total body fat [TBF (P = 0.002) and lower brain volume (P = 0.005)]. The same allele was also associated with higher lean body mass (P = 0.03) and no difference in height (P = 0.99). Principal component analysis identified a shared inverse variance between the brain volume and TBF, which was associated with FTO at P = 5.5 × 10(-6). These results were replicated in two independent samples of 413 and 718 adolescents, and in a meta-analysis of all three samples (n = 1729 adolescents), FTO was associated with this shared inverse variance at P = 1.3 × 10(-9). Co-expression networks analysis supported the possibility that the underlying FTO effects may occur during embryogenesis. In conclusion, FTO is associated with shared inverse variance between body adiposity and brain volume, suggesting that this gene may exert inverse effects on adipose and brain tissues. Given the completion of the overall brain growth in early childhood, these effects may have their origins during early development.
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http://dx.doi.org/10.1093/hmg/dds504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606009PMC
March 2013

Identification of common variants associated with human hippocampal and intracranial volumes.

Nat Genet 2012 Apr 15;44(5):552-61. Epub 2012 Apr 15.

Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).
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http://dx.doi.org/10.1038/ng.2250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635491PMC
April 2012

KCTD8 gene and brain growth in adverse intrauterine environment: a genome-wide association study.

Cereb Cortex 2012 Nov 9;22(11):2634-42. Epub 2011 Dec 9.

Rotman Research Institute, University of Toronto, Toronto, Ontario M6A 2E1, Canada.

The most dramatic growth of the human brain occurs in utero and during the first 2 years of postnatal life. Genesis of the cerebral cortex involves cell proliferation, migration, and apoptosis, all of which may be influenced by prenatal environment. Here, we show that variation in KCTD8 (potassium channel tetramerization domain 8) is associated with brain size in female adolescents (rs716890, P = 5.40 × 10(-09)). Furthermore, we found that the KCTD8 locus interacts with prenatal exposure to maternal cigarette smoking vis-à-vis cortical area and cortical folding: In exposed girls only, the KCTD8 locus explains up to 21% of variance. Using head circumference as a proxy of brain size at 7 years of age, we have replicated this gene-environment interaction in an independent sample. We speculate that KCTD8 might modulate adverse effects of smoking during pregnancy on brain development via apoptosis triggered by low intracellular levels of potassium, possibly reducing the number of progenitor cells.
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http://dx.doi.org/10.1093/cercor/bhr350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464418PMC
November 2012

Genome-wide scan for loci of adolescent obesity and their relationship with blood pressure.

J Clin Endocrinol Metab 2012 Jan 19;97(1):E145-50. Epub 2011 Oct 19.

The Hospital for Sick Children, Toronto, Canada.

Context: Hypertension, typically considered a disorder of adulthood, is now emerging in adolescence. This is mainly due to the growing prevalence of obesity and the fact that excess body fat increases blood pressure (BP).

Objective: The objective of the study was to investigate whether genome-wide identified gene loci of obesity are associated with elevated BP in adolescence.

Design: This was a genotype-phenotype association study.

Setting: The study was conducted in a French-Canadian founder population.

Participants: Participants included 598 adolescents, aged 12-18 yr.

Intervention: Testing associations between 530,011 single-nucleotide polymorphisms (SNP; Human610W-Quad BeadChip) and obesity measures and between identified SNP and BP.

Primary Outcome Measures: Total fat mass (TFM) was assessed with bioelectrical impedance, and body mass index (BMI) was determined with anthropometry. BP was measured beat by beat during an hour-long protocol.

Results: The genome-wide association studies of TFM and BMI revealed two novel and several previously identified loci of obesity. The former were PAX5 (rs16933812, TFM: P = 9.3 × 10(-9)) and MRPS22 (rs7638110, BMI: P = 4.6 × 10(-8)), and the top ones among the latter (P < 5 × 10(-4)) were MC4R (rs17773430, BMI: P = 5.8 × 10(-6)), FTO (rs9930333, BMI: P = 1.9 × 10(-4)), and MTCH2 (rs7120548, BMI: P = 1.9 × 10(-4)). From these five, only the PAX5, MRPS22, and FTO were also associated with BP; their minor allele homozygotes vs. major allele homozygotes showed greater TFM by 2.9-8.0 kg and higher BP by 3.3-6.7 mm Hg.

Conclusions: Genome-wide association studies conducted in an adolescent founder population revealed two new and a number of previously identified loci of obesity and demonstrated that several but not all of these loci are also associated with elevated BP. These results begin to reveal the genetic architecture of obesity-induced hypertension.
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http://dx.doi.org/10.1210/jc.2011-1801DOI Listing
January 2012

Genes, maternal smoking, and the offspring brain and body during adolescence: design of the Saguenay Youth Study.

Hum Brain Mapp 2007 Jun;28(6):502-18

Brain and Body Centre, University of Nottingham, Nottingham, United Kingdom.

The search for genes of complex traits is aided by the availability of multiple quantitative phenotypes collected in geographically isolated populations. Here we provide rationale for a large-scale study of gene-environment interactions influencing brain and behavior and cardiovascular and metabolic health in adolescence, namely the Saguenay Youth Study (SYS). The SYS is a retrospective study of long-term consequences of prenatal exposure to maternal cigarette smoking (PEMCS) in which multiple quantitative phenotypes are acquired over five sessions (telephone interview, home, hospital, laboratory, and school). To facilitate the search for genes that modify an individual's response to an in utero environment (i.e. PEMCS), the study is family-based (adolescent sibships) and is carried out in a relatively geographically isolated population of the Saguenay Lac-Saint-Jean (SLSJ) region in Quebec, Canada. DNA is acquired in both biological parents and in adolescent siblings. A genome-wide scan will be carried out with sib-pair linkage analyses, and fine mapping of identified loci will be done with family-based association analyses. Adolescent sibships (12-18 years of age; two or more siblings per family) are recruited in high schools throughout the SLSJ region; only children of French-Canadian origin are included. Based on a telephone interview, potential participants are classified as exposed or nonexposed prenatally to maternal cigarette smoking; the two groups are matched for the level of maternal education and the attended school. A total of 500 adolescent participants in each group will be recruited and phenotyped. The following types of datasets are collected in all adolescent participants: (1) magnetic resonance images of brain, abdominal fat, and kidneys, (2) standardized and computer-based neuropsychological tests, (3) hospital-based cardiovascular, body-composition and metabolic assessments, and (4) questionnaire-derived measures (e.g. life habits such as eating and physical activity; drug, alcohol use and delinquency; psychiatric symptoms; personality; home and school environment; academic and vocational attitudes). Parents complete a medical questionnaire, home-environment questionnaire, a handedness questionnaire, and a questionnaire about their current alcohol and drug use, depression, anxiety, and current and past antisocial behavior. To date, we have fully phenotyped a total of 408 adolescent participants. Here we provide the description of the SYS and, using the initial sample, we present information on ascertainment, demographics of the exposed and nonexposed adolescents and their parents, and the initial MRI-based assessment of familiality in the brain size and the volumes of grey and white matter.
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http://dx.doi.org/10.1002/hbm.20402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174527PMC
June 2007

Genome-wide scan for linkage to obesity-associated hypertension in French Canadians.

Hypertension 2005 Dec 10;46(6):1280-5. Epub 2005 Oct 10.

Brain and Body Centre, University of Nottingham, United Kingdom.

Essential hypertension is a heterogeneous disorder that is thought to develop because of several overlapping subsets of underlying mechanisms. One such causal pathway may involve pathophysiological alterations induced by obesity. In the present study, we examined whether investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, facilitates the search for its genes. Fifty-five extended families were selected on the basis of having > or =2 siblings affected by hypertension from a geographically remote French-Canadian population. Fifteen of these families showed a high prevalence (> or =70%) of obesity. Genome-wide scan using qualitative multipoint linkage analysis (GeneHunter 2.1; marker density <10 cM) was performed in the entire set of hypertensive families and the subset with high prevalence of obesity. In the scan involving all 55 families, the most significant loci (logarithm of odds [LOD] score=2.5) were identified on chromosomes 1 (D1S1597) and 11 (D11S1999). In the scan including only the subset of families with obesity-hypertension, the most significant locus (LOD score=3.1) was found on chromosome 1 in the same region as the scan involving all families (D1S1597). Genotyping additional markers increased the significance of this locus (LOD score=3.5) and refined its position (D1S2672). Several candidate genes of obesity-hypertension are located in close proximity; these include the tumor necrosis factor receptor 2 and atrial natriuretic peptide genes. These results suggest that investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, may facilitate the search for genes of this complex disorder.
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http://dx.doi.org/10.1161/01.HYP.0000188049.23233.fbDOI Listing
December 2005
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