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Yao N-J1, Chen WJ2,3,4, Hsieh W-S5, Lin C-H6, Tseng C-I2, Lin W-Y3, Kuo P-H3,7, Jeng S-F1,8
1National Taiwan University, School and Graduate Institute of Physical Therapy, Taipei, Taiwan, 2National Taiwan University, Genetic Epidemiology Core, Genetic Epidemiology Core, Center of Genomic Medicine, Taiwan, 3National Taiwan University, Institute of Epidemiology and Preventive Medicine, College of Public Health, Taipei, Taiwan, 4National Taiwan University Hospital, Department of Psychiatry, Taipei, Taiwan, 5National Taiwan University Hospital, Department of Pediatrics, Taipei, Taiwan, 6National Cheng Kung University, Department of Pediatrics, Tainan, Taiwan, 7National Taiwan University, Research Center for Genes, Environment and Human Health, Taipei, Taiwan, 8National Taiwan University Hospital, Physical Therapy Center, Taipei, Taiwan
Background: Previous studies have shown that dopamine-related genes are involved in neurotransmission in the nervous system of children with developmental disorders. Whether dopamine-related genes play a role in more common forms of developmental variation in preterm and term children remains unclear.
Purpose: This study aimed to examine the association of dopamine-related genes with mental and motor development, and the gene-environment interaction on development in preterm and term children from 6 to 36 months of age, and further replicate the findings in an independent sample.
Methods: The selection criteria for preterm children included birth weight 1,500 g, gestational age 37 weeks, and absence of congenital abnormality and severe neonatal diseases (e.g., hydrocephalus, periventricular leukomalacia, grade III-IV intraventricular hemorrhage, stage IV retinopathy of prematurity, necrotizing enterocolitis with colostomy, and severe cardiopulmonary disease requiring ventilator use at 44 weeks of post-menstrual age). A total of 201 preterm children and 111 term children were prospectively examined for their mental and motor development using the Bayley Scales of Infant Development - Second Edition at 6, 12, 18, 24, and 36 months of age, and buccal cell samples were collected for genotyping of 15 single-nucleotide polymorphisms (SNPs) including rs1800497, rs167771, rs27072, rs2550948, rs4818, rs4680, rs2075507, rs12843268, rs5905859, rs3027400, rs2235186, rs2235185, rs2072744, rs2239448, and rs3027407, which are located in five dopamine-related genes (DRD2, DRD3, DAT1, COMT and MAOA). An independent sample of 256 preterm children was used for replication. Mixed-effects models of longitudinal data using the intention-to-treat approach were used to analyze the repeated measures of each developmental outcome in relation to these SNPs in preterm and term children.
Results: Because preterm children exhibited different age trends in development from those of term children, the analyses were stratified by preterm and term birth. Of the 15 SNPs of dopamine-related genes, only the 8 SNPs of the MAOA gene were significantly associated with the mental scores of preterm children after false discovery rate corrections, with rs2239448 as the tag being the most significant for main effect (p = 0.0031) and interaction with age trend (p 0.0001; largest effect size of 0.65 at 24 months). Similar findings for rs2239448 were replicated in the independent sample (p = 0.02 and 0.03, respectively). However, none of the SNPs were associated with the motor scores of preterm children and none were related to the mental or motor scores of term children.
Conclusion(s): The genetic variants of the MAOA gene appear to yield influence on the mental development from 6 to 36 months of age for preterm, but not term, children. Moreover, our findings for the MAOA rs2239448 were robustly replicated in an independent preterm sample.
Implications: Our results provide important insights into the understanding of genetic influences on development in preterm children. Future research is warranted to investigate whether the MAOA variants can identify preterm children who may benefit most from early intervention to improve mental outcome.
Keywords: Gene, Child development, Preterm infants
Funding acknowledgements: Supported by National Health Research Institutes (NHRI-EX101-10106PI), Ministry of Science and Technology (105-2314-B-002-017), and National Taiwan University Hospital (NTUH-98-S-1085), Taiwan.
Purpose: This study aimed to examine the association of dopamine-related genes with mental and motor development, and the gene-environment interaction on development in preterm and term children from 6 to 36 months of age, and further replicate the findings in an independent sample.
Methods: The selection criteria for preterm children included birth weight 1,500 g, gestational age 37 weeks, and absence of congenital abnormality and severe neonatal diseases (e.g., hydrocephalus, periventricular leukomalacia, grade III-IV intraventricular hemorrhage, stage IV retinopathy of prematurity, necrotizing enterocolitis with colostomy, and severe cardiopulmonary disease requiring ventilator use at 44 weeks of post-menstrual age). A total of 201 preterm children and 111 term children were prospectively examined for their mental and motor development using the Bayley Scales of Infant Development - Second Edition at 6, 12, 18, 24, and 36 months of age, and buccal cell samples were collected for genotyping of 15 single-nucleotide polymorphisms (SNPs) including rs1800497, rs167771, rs27072, rs2550948, rs4818, rs4680, rs2075507, rs12843268, rs5905859, rs3027400, rs2235186, rs2235185, rs2072744, rs2239448, and rs3027407, which are located in five dopamine-related genes (DRD2, DRD3, DAT1, COMT and MAOA). An independent sample of 256 preterm children was used for replication. Mixed-effects models of longitudinal data using the intention-to-treat approach were used to analyze the repeated measures of each developmental outcome in relation to these SNPs in preterm and term children.
Results: Because preterm children exhibited different age trends in development from those of term children, the analyses were stratified by preterm and term birth. Of the 15 SNPs of dopamine-related genes, only the 8 SNPs of the MAOA gene were significantly associated with the mental scores of preterm children after false discovery rate corrections, with rs2239448 as the tag being the most significant for main effect (p = 0.0031) and interaction with age trend (p 0.0001; largest effect size of 0.65 at 24 months). Similar findings for rs2239448 were replicated in the independent sample (p = 0.02 and 0.03, respectively). However, none of the SNPs were associated with the motor scores of preterm children and none were related to the mental or motor scores of term children.
Conclusion(s): The genetic variants of the MAOA gene appear to yield influence on the mental development from 6 to 36 months of age for preterm, but not term, children. Moreover, our findings for the MAOA rs2239448 were robustly replicated in an independent preterm sample.
Implications: Our results provide important insights into the understanding of genetic influences on development in preterm children. Future research is warranted to investigate whether the MAOA variants can identify preterm children who may benefit most from early intervention to improve mental outcome.
Keywords: Gene, Child development, Preterm infants
Funding acknowledgements: Supported by National Health Research Institutes (NHRI-EX101-10106PI), Ministry of Science and Technology (105-2314-B-002-017), and National Taiwan University Hospital (NTUH-98-S-1085), Taiwan.
Topic: Paediatrics; Mental health; Intellectual disability
Ethics approval required: Yes
Institution: National Taiwan University Hospital
Ethics committee: Medical ethics committee
Ethics number: Identifier on ClinicalTrials.gov: NCT00173108, NCT00946244, and NCT01807533
All authors, affiliations and abstracts have been published as submitted.
