DGKK was the main gene found to be associated with hypospadias in a genome-wide association study (GWAS) (van der Zanden et al., 2011), which we replicated in a further study (Carmichael et al., 2013). Given that DGKK is expressed in the placenta (we know little else about it), and hypospadias is associated with fetal growth retardation (Carmichael et al., 2012), we hypothesized that DGKK variants would be associated with fetal growth. Preliminary data among 930 non-malformed, male, population-based controls that were part of our DGKK-hypospadias study suggest that DGKK variants are associated with increased risk of low birthweight (less than 2500 gm) among term infants (37 or more weeks gestation). However, the sample size was relatively limited (only 20 subjects were term and low birthweight). ALSPAC offers an excellent opportunity to examine this hypothesis in more depth and in a much larger sample (approximately 7,500 subjects).

Our hypothesis is that DGKK is associated with fetal growth. The aim of the proposed analysis is to examine the association of fetal growth with infant genetic variants (SNPs) in DGKK that were included in the Illumina 317 genotyping (GWAS) panel, which has been run on ALSPAC samples. Parameters reflecting fetal growth, as well exclusion criteria for genotyping data, will largely follow methods developed for use of ALSPAC data for the meta-analysis of GWAS data on fetal growth by Freathy et al. (2010). That is, we will examine the association of birthweight standardized to z scores adjusted for gestational age, as a continuous measure and as a dichotomy (ie, less than 10th percentile versus higher), and we will examine birth length, head circumference and ponderal index, all among singleton term infants. The Freathy et al. study did not examine growth among preterm infants, but we propose to also examine the association of the DGKK variants with preterm delivery and with birthweight adjusted for gestational age among infants born preterm. All analyses will be stratified by infant sex since DGKK is on the X chromosome. Potential covariates to consider inclue maternal age, parity, prepregnancy body mass index, smoking, and education (as a marker of socioeconomic status). We will restrict analyses to singletons.

References

Carmichael SL, Mohammed N, Ma C, Iovannisci D, Choudhry S, Baskin LS, Witte JS, Shaw GM, Lammer EJ. Diacylglycerol kinase K variants impact hypospadias in a California study population. J Urol 2013;189:305-11.

Carmichael SL, Shaw GM, Lammer EJ. Environmental and genetic contributors to hypospadias: a review of the epidemiologic evidence. Birth Defects Res A Clin Mol Teratol 2012;94:499-510.

Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, et al. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet 2010;42:430-5.

van der Zanden LF, van Rooij IA, Feitz WF, Knight J, Donders AR, et al. Common variants in DGKK are strongly associated with risk of hypospadias. Nat Genet. 2011;43:48-50.