Individuals carrying the same pathogenic mutation can present with a broad range of disease outcomes. While some of this variation arises from environmental factors, it is increasingly recognized that the background genetic variation of each individual can have a profound effect on the expressivity of a pathogenic mutation. In order to understand this background effect on disease-causing mutations, studies need to be performed across a wide range of backgrounds. Recent advancements in model organism biology allow us to test mutations across genetically diverse backgrounds and identify the genes that influence the expressivity of a mutation. In this study, we used the Drosophila Genetic Reference Panel, a collection of ∼200 wild-derived strains, to test the variability of the retinal phenotype of the Rh1(G69D) Drosophila model of retinitis pigmentosa (RP). We found that the Rh1(G69D) retinal phenotype is quite a variable quantitative phenotype. To identify the genes driving this extensive phenotypic variation, we performed a genome-wide association study. We identified 106 candidate genes, including 14 high-priority candidates. Functional testing by RNAi indicates that 10/13 top candidates tested influence the expressivity of Rh1(G69D). The human orthologs of the candidate genes have not previously been implicated as RP modifiers and their functions are diverse, including roles in endoplasmic reticulum stress, apoptosis and retinal degeneration and development. This study demonstrates the utility of studying a pathogenic mutation across a wide range of genetic backgrounds. These candidate modifiers provide new avenues of inquiry that may reveal new RP disease mechanisms and therapies.

Patent ductus arteriosus (PDA) is a common morbidity associated with preterm birth. The incidence of PDA increases with decreasing gestational age to about 70% in infants born at 25 weeks gestation. Although medical treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is used to close the ductus arteriosus, approximately 30% of infants with a PDA do not respond to pharmacologic attempts at closure. We investigated whether single nucleotide polymorphisms (SNPs) in genes that regulate smooth muscle contraction, xenobiotic detoxification, inflammation and other processes are markers for persistent patency of the DA. Initially, 377 SNPs from 130 genes of interest were evaluated in DNA samples collected from 204 infants with a gestational age of less than 32 weeks. A family-based association test (FBAT) was performed on genotyping data to evaluate overtransmission of alleles. P-values of less than 0.01 were detected for genetic variations found in seven genes. The analysis was then replicated with an independent set of 162 infants, focusing on the seven markers with initial p-values less than 0.01, and one genetic variant in the angiotensin II type I receptor (AGTR1) previously shown to be related to PDA. Of the initial positive signals, SNPs in the transcription factor AP-2 beta (TFAP2B) and TNF receptor-associated factor 1 (TRAF1) genes remained significant, both with p-values of 0.005. An AGTR1 polymorphism previously reported to be associated with PDA following prophylactic indomethacin administration was not associated with the presence of a PDA in our population (p = 0.48). Overall, our data support a role for a genetic contribution to the risk of PDAs in preterm infants.

Intraventricular hemorrhage (IVH) is a significant morbidity seen in very low birth weight infants. Genes related to the inflammation, infection, complement or coagulation pathways have been implicated as risk factors for IVH. We examined ten candidate genes for associations with IVH in 271 preterm infants (64 with IVH grade I-IV and 207 without IVH) weighing less than 1,500 grams. The heterozygous genotype (odds ratio (OR)=8.1, confidence interval (CI)=2.5–26.0, p=4×10−4) and the A allele (OR=7.3, CI=2.4–22.5, p=1×10−4) of the coagulation factor V (FV) Leiden mutation (rs6025) were associated with an increased risk of developing IVH grade I or II but not grades III or IV after correction for multiple testing with Bonferroni. Lack of association in the severe grades of IVH may be a result of lack of power to detect an effect given the small sample size (n=8). However, this result is consistent with previous research that demonstrates that the heterozygous genotype of the FV mutation is associated with increased risk for the development of IVH but a decreased risk for the progression or extension to more severe grades of IVH.

Objective To investigate genetic etiologies of preterm birth (PTB) in Argentina through evaluation of single-nucleotide polymorphisms (SNP) in candidate genes and population genetic admixture. Study Design Genotyping was performed in 389 families. Maternal, paternal, and fetal effects were studied separately. Mitochondrial DNA (mtDNA) was sequenced in 50 males and 50 females. Y-chromosome anthropological markers were evaluated in 50 males. Results Fetal association with PTB was found in the progesterone receptor (PGR, rs1942836; p= 0.004). Maternal association with PTB was found in small conductance calcium activated potassium channel isoform 3 (KCNN3, rs883319; p= 0.01). Gestational age associated with PTB in PGR rs1942836 at 32 –36 weeks (p= 0.0004). MtDNA sequencing determined 88 individuals had Amerindian consistent haplogroups. Two individuals had Amerindian Y-chromosome consistent haplotypes. Conclusions This study replicates single locus fetal associations with PTB in PGR, maternal association in KCNN3, and demonstrates possible effects for divergent racial admixture on PTB.