Results of genome-wide analyses on neurodevelopmental phenotypes at four-year follow-up following cardiac surgery in infancy.
BACKGROUND
Adverse neurodevelopmental sequelae are reported among children who undergo early cardiac surgery to repair congenital heart defects (CHD). APOE genotype has previously been determined to contribute to the prediction of these outcomes. Understanding further genetic causes for the development of poor neurobehavioral outcomes should enhance patient risk stratification and improve both prevention and treatment strategies.


METHODS
We performed a prospective observational study of children who underwent cardiac surgery before six months of age; this included a neurodevelopmental evaluation between their fourth and fifth birthdays. Attention and behavioral skills were assessed through parental report utilizing the Attention Deficit-Hyperactivity Disorder-IV scale preschool edition (ADHD-IV), and Child Behavior Checklist (CBCL/1.5-5), respectively. Of the seven investigated, three neurodevelopmental phenotypes met genomic quality control criteria. Linear regression was performed to determine the effect of genome-wide genetic variation on these three neurodevelopmental measures in 316 subjects.


RESULTS
This genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with three neurobehavioral phenotypes in the postoperative children ADHD-IV Impulsivity/Hyperactivity, CBCL/1.5-5 PDPs, and CBCL/1.5-5 Total Problems. The most predictive SNPs for each phenotype were: a LGALS8 intronic SNP, rs4659682, associated with ADHD-IV Impulsivity (P=1.03 × 10(-6)); a PCSK5 intronic SNP, rs2261722, associated with CBCL/1.5-5 PDPs (P=1.11 × 10(-6)); and an intergenic SNP, rs11617488, 50 kb from FGF9, associated with CBCL/1.5-5 Total Problems (P=3.47 × 10(-7)). 10 SNPs (3 for ADHD-IV Impulsivity, 5 for CBCL/1.5-5 PDPs, and 2 for CBCL/1.5-5 Total Problems) had p<10(-5).


CONCLUSIONS
No SNPs met genome-wide significance for our three neurobehavioral phenotypes; however, 10 SNPs reached a threshold for suggestive significance (p<10(-5)). Given the unique nature of this cohort, larger studies and/or replication are not possible. Studies to further investigate the mechanisms through which these newly identified genes may influence neurodevelopment dysfunction are warranted.
Department of Medicine, Division of Medical Genetics, University of Washington School of Medicine, Seattle, Washington, USA.
Daniel S
DS
Kim
Ian B
IB
Stanaway
Ramakrishnan
R
Rajagopalan
Judy C
JC
Bernbaum
Cynthia B
CB
Solot
Nancy
N
Burnham
Elaine H
EH
Zackai
Robert R
RR
Clancy
Susan C
SC
Nicolson
Marsha
M
Gerdes
Deborah A
DA
Nickerson
Hakon
H
Hakonarson
J William
JW
Gaynor
Gail P
GP
Jarvik
D001057:Apolipoproteins E / Q000235:genetics; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics; D006348:Cardiac Surgical Procedures / Q000379:methods; D002653:Child Behavior Disorders / Q000235:genetics; D002675:Child, Preschool; D015331:Cohort Studies; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study; D005838:Genotype; D006331:Heart Diseases / Q000601:surgery; D006801:Humans; D008297:Male; D008957:Models, Genetic; D010641:Phenotype; D011446:Prospective Studies; D012306:Risk; D016896:Treatment Outcome
D001057:Apolipoproteins E