Genetic Influences on Preterm Birth

Preterm birth: PTB) is a leading cause of mortality and disease burden globally; however, determinants of human parturition remain largely uncharacterized, making prediction and prevention of difficult. Genetic studies are one way in which we can attempt to better understand this disorder. We first sought to develop a model for the genetic influences on PTB to facilitate gene discovery. Study of standard measures of familial aggregation, the sibling risk ratio and the sibling-sibling odds ratio, and segregation analyses of gestational age, a quantitative proxy for preterm birth, lend support to a genetic component contributing to birth timing, since preterm deliveries cluster in families and models in which environmental factors alone contribute to gestational age are strongly rejected. Analyses of gestational age attributed to the infant support a model in which mother\u27s genome and/or maternally-inherited genes acting in the fetus are largely responsible for birth timing. We also aimed to discover specific genes associated with PTB by screening genes selected based on an evolutionary-motivated filter, rather than known parturition physiology. Because humans are born developmentally less mature than other mammals, birth timing mechanisms may differ between humans and model organisms that have been typically studied; as a result, we screened 150 genes, selected because of their rapid evolution along the human lineage. A screen of over 8000 SNPs in 165 Finnish preterm and 163 control mothers identified an enrichment of variants in FSHRassociated with PTB and prompted further study of the gene. Additionally, PLA2G4C, identified as the gene with the most statistically significant evidence for rapid evolution that was also included in a list of preterm birth candidate genes, was examined further. Three SNPs in PLA2G4C and one SNP in FSHR were statistically significant across populations after multiple testing corrections. Additional work to identify variants in these genes with functional effects was also initiated, including comparisons of prostaglandin metabolite levels among genotype classes for significantly associated SNPs in PLA2G4C and sequencing of FSHR to identify functional coding variants. Together, these experiments better characterize the nature of genetic influences on PTB and support the role of PLA2G4C and FSHR in PTB

Population-based estimate of sibling risk for preterm birth, preterm premature rupture of membranes, placental abruption and pre-eclampsia

<p>Abstract</p> <p>Background</p> <p>Adverse pregnancy outcomes, such as preterm birth, preeclampsia and placental abruption, are common, with acute and long-term complications for both the mother and infant. Etiologies underlying such adverse outcomes are not well understood. As maternal and fetal genetic factors may influence these outcomes, we estimated the magnitude of familial aggregation as one index of possible heritable contributions.</p> <p>Using the Missouri Department of Health's maternally-linked birth certificate database, we performed a retrospective population-based cohort study of births (1989–1997), designating an individual born from an affected pregnancy as the proband for each outcome studied. We estimated the increased risk to siblings compared to the population risk, using the sibling risk ratio, λ_s, and sibling-sibling odds ratio (sib-sib OR), for the adverse pregnancy outcomes of preterm birth, preterm premature rupture of membranes (PPROM), placental abruption, and pre-eclampsia.</p> <p>Results</p> <p>Risk to siblings of an affected individual was elevated above the population prevalence of a given disorder, as indicated by λ_S(λ_S(95% CI): 4.3 (4.0–4.6), 8.2 (6.5–9.9), 4.0 (2.6–5.3), and 4.5 (4.4–4.8), for preterm birth, PPROM, placental abruption, and pre-eclampsia, respectively). Risk to siblings of an affected individual was similarly elevated above that of siblings of unaffected individuals, as indicated by the sib-sib OR (sib-sib OR adjusted for known risk factors (95% CI): 4.2 (3.9–4.5), 9.6 (7.6–12.2), 3.8 (2.6–5.5), 8.1 (7.5–8.8) for preterm birth, PPROM, placental abruption, and pre-eclampsia, respectively).</p> <p>Conclusion</p> <p>These results suggest that the adverse pregnancy outcomes of preterm birth, PPROM, placental abruption, and pre-eclampsia aggregate in families, which may be explained in part by genetics.</p

Fine-Mapping an Association of FSHR with Preterm Birth in a Finnish Population

Peer reviewe

A framework for analyzing both linkage and association: An analysis of Genetic Analysis Workshop 16 simulated data

We examine a Bayesian Markov-chain Monte Carlo framework for simultaneous segregation and linkage analysis in the simulated single-nucleotide polymorphism data provided for Genetic Analysis Workshop 16. We conducted linkage only, linkage and association, and association only tests under this framework. We also compared these results with variance-component linkage analysis and regression analyses. The results indicate that the method shows some promise, but finding genes that have very small (<0.1%) contributions to trait variance may require additional sources of information. All methods examined fared poorly for the smallest in the simulated "polygene" range (h(2 )of 0.0015 to 0.0002)

A Potential Novel Spontaneous Preterm Birth Gene, AR, Identified by Linkage and Association Analysis of X Chromosomal Markers

Peer reviewe

Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis

Peer reviewe

Primate-specific evolution of noncoding element insertion into PLA2G4C and human preterm birth

Background The onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. We hypothesize that higher primate-specific gene evolution may lead to these differences and target genes involved in human preterm birth, an area of global health significance. Methods We performed a comparative genomics screen of highly conserved noncoding elements and identified PLA2G4C, a phospholipase A isoform involved in prostaglandin biosynthesis as human accelerated. To examine whether this gene demonstrating primate-specific evolution was associated with birth timing, we genotyped and analyzed 8 common single nucleotide polymorphisms (SNPs) in PLA2G4C in US Hispanic (n = 73 preterm, 292 control), US White (n = 147 preterm, 157 control) and US Black (n = 79 preterm, 166 control) mothers. Results Detailed structural and phylogenic analysis of PLA2G4C suggested a short genomic element within the gene duplicated from a paralogous highly conserved element on chromosome 1 specifically in primates. SNPs rs8110925 and rs2307276 in US Hispanics and rs11564620 in US Whites were significant after correcting for multiple tests (p < 0.006). Additionally, rs11564620 (Thr360Pro) was associated with increased metabolite levels of the prostaglandin thromboxane in healthy individuals (p = 0.02), suggesting this variant may affect PLA2G4C activity. Conclusions Our findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.Children’s Discovery InstituteMarch of Dimes Birth Defects FoundationNational Institute of General Medical Sciences (U.S.) (grant T32 GM081739)Washington University (Saint Louis, Mo.) (Mr. and Mrs. Spencer T. Olin Fellowship for Women in Graduate Study)Sigrid Jusélius FoundationSigne and Anne Gyllenberg FoundationAcademy of FinlandVanderbilt University (Turner-Hazinski grant award

An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing

Peer reviewe

Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study

Peer reviewe

Training future physicians in the era of genomic medicine: trends in undergraduate medical genetics education

PURPOSE: Advances in genomic technologies are transforming medical practice, necessitating the expertise of genomically-literate physicians. This study examined 2013-2014 trends in genetics curricula in US and Canadian medical schools to ascertain whether and how curricula are keeping pace with this rapid evolution. METHODS: Medical genetics course directors received a 60-item electronic questionnaire covering curriculum design, assessment, remediation of failing grades, and inclusion of specific topics. RESULTS: The response rate was 74%. Most schools teach the majority of genetics during the first 2 years, with an increase in the number of integrated curricula. Only 26% reported formal genetics teaching during years 3 and 4, and most respondents felt the amount of time spent on genetics was insufficient preparation for clinical practice. Most participants are using the Association of Professors of Human and Medical Genetics Core Curriculum(1) as a guide. Topics recently added include personalized medicine (21%) and direct-to-consumer testing (18%), whereas eugenics (17%), linkage analysis (16%), and evolutionary genetics (15%) have been recently eliminated. Remediation strategies were heterogeneous across institutions. CONCLUSION: These findings provide an important update on how genetics and genomics is taught at US and Canadian medical schools. Continuous improvement of educational initiatives will aid in producing genomically-literate physicians