Abstract
Genome-wide association studies (GWASs) are unraveling the genetics of adult brain neuroanatomy as measured by cross-sectional anatomic magnetic resonance imaging (aMRI). However, the genetic mechanisms that shape childhood brain development are, as yet, largely unexplored. In this study we identify common genetic variants associated with childhood brain development as defined by longitudinal aMRI. Genome-wide single nucleotide polymorphism (SNP) data were determined in two cohorts: one enriched for attention-deficit/hyperactivity disorder (ADHD) (LONG cohort: 458 participants; 119 with ADHD) and the other from a population-based cohort (Generation R: 257 participants). The growth of the brain's major regions (cerebral cortex, white matter, basal ganglia, and cerebellum) and one region of interest (the right lateral prefrontal cortex) were defined on all individuals from two aMRIs, and a GWAS and a pathway analysis were performed. In addition, association between polygenic risk for ADHD and brain growth was determined for the LONG cohort. For white matter growth, GWAS meta-analysis identified a genome-wide significant intergenic SNP (rs12386571, P = 9.09 × 10−9), near AKR1B10. This gene is part of the aldo-keto reductase superfamily and shows neural expression. No enrichment of neural pathways was detected and polygenic risk for ADHD was not associated with the brain growth phenotypes in the LONG cohort that was enriched for the diagnosis of ADHD. The study illustrates the use of a novel brain growth phenotype defined in vivo for further study.
| Original language | English |
|---|---|
| Pages (from-to) | 405-414 |
| Number of pages | 10 |
| Journal | Genetic Epidemiology |
| Volume | 42 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Jun 2018 |
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Genetic associations with childhood brain growth, defined in two longitudinal cohorts. / Szekely, Eszter; Schwantes-An, Tae Hwi Linus; Justice, Cristina M. et al.
In: Genetic Epidemiology, Vol. 42, No. 4, 06.2018, p. 405-414.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Genetic associations with childhood brain growth, defined in two longitudinal cohorts
AU - Szekely, Eszter
AU - Schwantes-An, Tae Hwi Linus
AU - Justice, Cristina M.
AU - Sabourin, Jeremy A.
AU - Jansen, Philip R.
AU - Muetzel, Ryan L.
AU - Sharp, Wendy
AU - Tiemeier, Henning
AU - Sung, Heejong
AU - White, Tonya J.
AU - Wilson, Alexander F.
AU - Shaw, Philip
N1 - Funding Information: The LONG Study was funded by the Intramural Programs of the National Human Genome Research Institute (NHGRI) and National Institute of Mental Health (NIMH). The authors gratefully acknowledge the participation of all children and families in the study. Genotyping services for the LONG cohort were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268201200008I. This project was also supported in part by the Division of Intramural Research Program of NHGRI. Analysis of the Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the Erasmus University Rotterdam, the Municipal Health Service in the Rotterdam area, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst and Artsenlaboratorium Rijn-mond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of general practitioners, hospitals, midwives, and pharmacies in Rotterdam. Neuroimaging studies within the Generation R are supported through the Netherlands Organization for Health Research and Development (NWO) (ZonMw TOP 40-00812-98-11021), the European Community's Seventh Framework Program (FP7/2008–2013) under grant agreement 212652 (NUTRIMENTHE), the Sticht-ing Sophia Kinderziekenhuis Fonds, and General Electric Healthcare. The Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, ZonMw (ZonMW 10.000.1003), NWO, the Ministry of Health, Welfare and Sport, and the Ministry of Youth and Families. Funding Information: The LONG Study was funded by the Intramural Programs of the National Human Genome Research Institute (NHGRI) and National Institute of Mental Health (NIMH). The authors gratefully acknowledge the participation of all children and families in the study. Genotyping services for the LONG cohort were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268201200008I. This project was also supported in part by the Division of Intramural Research Program of NHGRI. Analysis of the Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the Erasmus University Rotterdam, the Municipal Health Service in the Rotterdam area, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst and Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of general practitioners, hospitals, midwives, and pharmacies in Rotterdam. Neuroimaging studies within the Generation R are supported through the Netherlands Organization for Health Research and Development (NWO) (ZonMw TOP 40-00812-98-11021), the European Community's Seventh Framework Program (FP7/2008?2013) under grant agreement 212652 (NUTRIMENTHE), the Stichting Sophia Kinderziekenhuis Fonds, and General Electric Healthcare. The Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, ZonMw (ZonMW 10.000.1003), NWO, the Ministry of Health, Welfare and Sport, and the Ministry of Youth and Families. Publisher Copyright: Published 2018. This article is a U.S. Government work and is in the public domain in the USA. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/6
Y1 - 2018/6
N2 - Genome-wide association studies (GWASs) are unraveling the genetics of adult brain neuroanatomy as measured by cross-sectional anatomic magnetic resonance imaging (aMRI). However, the genetic mechanisms that shape childhood brain development are, as yet, largely unexplored. In this study we identify common genetic variants associated with childhood brain development as defined by longitudinal aMRI. Genome-wide single nucleotide polymorphism (SNP) data were determined in two cohorts: one enriched for attention-deficit/hyperactivity disorder (ADHD) (LONG cohort: 458 participants; 119 with ADHD) and the other from a population-based cohort (Generation R: 257 participants). The growth of the brain's major regions (cerebral cortex, white matter, basal ganglia, and cerebellum) and one region of interest (the right lateral prefrontal cortex) were defined on all individuals from two aMRIs, and a GWAS and a pathway analysis were performed. In addition, association between polygenic risk for ADHD and brain growth was determined for the LONG cohort. For white matter growth, GWAS meta-analysis identified a genome-wide significant intergenic SNP (rs12386571, P = 9.09 × 10−9), near AKR1B10. This gene is part of the aldo-keto reductase superfamily and shows neural expression. No enrichment of neural pathways was detected and polygenic risk for ADHD was not associated with the brain growth phenotypes in the LONG cohort that was enriched for the diagnosis of ADHD. The study illustrates the use of a novel brain growth phenotype defined in vivo for further study.
AB - Genome-wide association studies (GWASs) are unraveling the genetics of adult brain neuroanatomy as measured by cross-sectional anatomic magnetic resonance imaging (aMRI). However, the genetic mechanisms that shape childhood brain development are, as yet, largely unexplored. In this study we identify common genetic variants associated with childhood brain development as defined by longitudinal aMRI. Genome-wide single nucleotide polymorphism (SNP) data were determined in two cohorts: one enriched for attention-deficit/hyperactivity disorder (ADHD) (LONG cohort: 458 participants; 119 with ADHD) and the other from a population-based cohort (Generation R: 257 participants). The growth of the brain's major regions (cerebral cortex, white matter, basal ganglia, and cerebellum) and one region of interest (the right lateral prefrontal cortex) were defined on all individuals from two aMRIs, and a GWAS and a pathway analysis were performed. In addition, association between polygenic risk for ADHD and brain growth was determined for the LONG cohort. For white matter growth, GWAS meta-analysis identified a genome-wide significant intergenic SNP (rs12386571, P = 9.09 × 10−9), near AKR1B10. This gene is part of the aldo-keto reductase superfamily and shows neural expression. No enrichment of neural pathways was detected and polygenic risk for ADHD was not associated with the brain growth phenotypes in the LONG cohort that was enriched for the diagnosis of ADHD. The study illustrates the use of a novel brain growth phenotype defined in vivo for further study.
KW - ADHD
KW - brain development
KW - children
KW - GWAS
KW - pathway analysis
KW - polygenic score
UR - http://www.scopus.com/inward/record.url?scp=85045838954&partnerID=8YFLogxK
U2 - 10.1002/gepi.22122
DO - 10.1002/gepi.22122
M3 - Article
C2 - 29682794
AN - SCOPUS:85045838954
VL - 42
SP - 405
EP - 414
JO - Genetic Epidemiology
JF - Genetic Epidemiology
SN - 0741-0395
IS - 4
ER -