Powerful and robust cross-phenotype association test for case-parent trios.

There has been increasing interest in identifying genes within the human genome that influence multiple diverse phenotypes. In the presence of pleiotropy, joint testing of these phenotypes is not only biologically meaningful but also statistically more powerful than univariate analysis of each separate phenotype accounting for multiple testing. Although many cross-phenotype association tests exist, the majority of such methods assume samples composed of unrelated subjects and therefore are not applicable to family-based designs, including the valuable case-parent trio design. In this paper, we describe a robust gene-based association test of multiple phenotypes collected in a case-parent trio study. Our method is based on the kernel distance covariance (KDC) method, where we first construct a similarity matrix for multiple phenotypes and a similarity matrix for genetic variants in a gene; we then test the dependency between the two similarity matrices. The method is applicable to either common variants or rare variants in a gene, and resulting tests from the method are by design robust to confounding due to population stratification. We evaluated our method through simulation studies and observed that the method is substantially more powerful than standard univariate testing of each separate phenotype. We also applied our method to phenotypic and genotypic data collected in case-parent trios as part of the Genetics of Kidneys in Diabetes (GoKinD) study and identified a genome-wide significant gene demonstrating cross-phenotype effects that was not identified using standard univariate approaches.

Leveraging Family History in Case-Control Analyses of Rare Variation.

Standard methods for case-control association studies of rare variation often treat disease outcome as a dichotomous phenotype. However, both theoretical and experimental studies have demonstrated that subjects with a family history of disease can be enriched for risk variation relative to subjects without such history. Assuming family history information is available, this observation motivates the idea of replacing the standard dichotomous outcome variable used in case-control studies with a more informative ordinal outcome variable that distinguishes controls (0), sporadic cases (1), and cases with a family history (2), with the expectation that we should observe increasing number of risk variants with increasing category of the ordinal variable. To leverage this expectation, we propose a novel rare-variant association test that incorporates family history information based on our previous GAMuT framework for rare-variant association testing of multivariate phenotypes. We use simulated data to show that, when family history information is available, our new method outperforms standard rare-variant association methods, like burden and SKAT tests, that ignore family history. We further illustrate our method using a rare-variant study of cleft lip and palate.

Developmental Outcomes in Duarte Galactosemia.

: media-1vid110.1542/5849572227001PEDS-VA_2018-2516Video Abstract OBJECTIVES: For decades, infants with Duarte galactosemia (DG) have been identified by newborn screening (NBS), but whether they should be treated with dietary restrictions of galactose has remained unknown. To clarify, we conducted a study of dietary and developmental outcomes in 206 children with DG (case patients) and 144 controls, all of whom were 6 to 12 years old. METHODS: We recruited case patients from states where they were identified by NBS; unaffected siblings served as controls. Diet in infancy was ascertained by retrospective parent surveys; developmental outcomes were assessed in 5 domains, yielding 73 outcome measures for each child. We divided subjects randomly into independent discovery (n = 87) and validation (n = 263) sets. We tested the discovery set to order the 73 outcome measures by ascending P values and tested the 10 outcomes with the lowest P values for possible association with DG in the validation set. We also tested these same 10 outcomes for possible association with milk exposure in infancy among case patients in the validation set. RESULTS: None of the 73 outcomes tested in the discovery set revealed significant association with DG, and none of the 10 outcomes tested in the validation set revealed either significant association with DG or significant association with milk exposure among children with DG. CONCLUSIONS: Through our results, we demonstrated that there were no significant differences in outcomes tested between case patients and controls or among case patients as a function of milk exposure in infancy. In this study, we provide a long-needed foundation of knowledge for health care providers, families, and NBS professionals seeking to make evidence-based decisions about DG.

Low-level maternal exposure to nicotine associates with significant metabolic perturbations in second-trimester amniotic fluid.

Decades of public health research have documented that smoking in pregnancy poses significant health risks to both mother and child. More recent studies have shown that even passive maternal exposure to secondhand smoke associates with negative birth outcomes. However, the mechanisms linking exposure to outcomes have remained obscure. As a first step toward defining the metabolic consequence of low-level nicotine exposure on fetal development, we conducted an untargeted metabolomic analysis of 81 paired samples of maternal serum and amniotic fluid collected from karyotypically normal pregnancies in the second trimester. By comparing the m/z and retention times of our mass spectral features with confirmed standards, we identified cotinine, a nicotine derivative, and used the calculated cotinine concentrations to classify our maternal serum samples into exposure groups using previously defined cut-offs. We found that cotinine levels consistent with low-level maternal exposure to nicotine associated with distinct metabolic perturbations, particularly in amniotic fluid. In fact, the metabolic effects in amniotic fluid of ostensibly low-level exposed mothers showed greater overlap with perturbations previously observed in the sera of adult smokers than did the perturbations observed in the corresponding maternal sera. Dysregulated fetal pathways included aspartate and asparagine metabolism, pyrimidine metabolism, and metabolism of other amino acids. We also observed a strong negative association between level of maternal serum cotinine and acetylated polyamines in the amniotic fluid. Combined, these results confirm that low-level maternal nicotine exposure, indicated by a maternal serum cotinine level of 2-10ng/mL, is associated with striking metabolic consequences in the fetal compartment, and that the affected pathways overlap those perturbed in the sera of adult smokers.