Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits

Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets

To provide better prevention and treatment, we need to understand the environmental and genetic risks of Alzheimer’s disease (AD). However, the definition of AD has been confounded with dementia in many studies. Thus, overinterpretation of genetic findings with regard to mechanisms and drug targets may explain, in part, controversies in the field. Here, we analyze the different forms of genetic risk of AD and how these can be used to model disease. We stress the importance of studying gene variants in the right cell types and in the right pathological context. The lack of mechanistic understanding of genetic variation has become the major bottleneck in the search for new drug targets for AD

The multiplex model of the genetics of Alzheimer’s disease

Genes play a strong role in Alzheimer’s disease (AD) with late-onset AD showing heritability of 58-79% and early-onset AD over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 40 loci are now implicated for AD, suggesting that AD is a disease of multiple components as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD (LOAD) heritability has been captured and allows the calculation of the accumulation of AD genetic risk through polygenic risk scores (PRS). PRS predicts disease with up to 90% accuracy and is an exciting tool in our research armoury that could allow selection of those with high PRS for clinical trials and precision medicine, as well as the cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflex’s the combination of some, or all, of these model components (genetic and environmental), in a tissue specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell/synaptic loss observed in AD

System-Level Analysis of Alzheimer\u27s Disease Prioritizes Candidate Genes for Neurodegeneration.

Alzheimer\u27s disease (AD) is a debilitating neurodegenerative disorder. Since the advent of the genome-wide association study (GWAS) we have come to understand much about the genes involved in AD heritability and pathophysiology. Large case-control meta-GWAS studies have increased our ability to prioritize weaker effect alleles, while the recent development of network-based functional prediction has provided a mechanism by which we can use machine learning to reprioritize GWAS hits in the functional context of relevant brain tissues like the hippocampus and amygdala. In parallel with these developments, groups like the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) have compiled rich compendia of AD patient data including genotype and biomarker information, including derived volume measures for relevant structures like the hippocampus and the amygdala. In this study we wanted to identify genes involved in AD-related atrophy of these two structures, which are often critically impaired over the course of the disease. To do this we developed a combined score prioritization method which uses the cumulative distribution function of a gene\u27s functional and positional score, to prioritize top genes that not only segregate with disease status, but also with hippocampal and amygdalar atrophy. Our method identified a mix of genes that had previously been identified in AD GWAS including APOE, TOMM40, and NECTIN2(PVRL2) and several others that have not been identified in AD genetic studies, but play integral roles in AD-effected functional pathways including IQSEC1, PFN1, and PAK2. Our findings support the viability of our novel combined score as a method for prioritizing region- and even cell-specific AD risk genes

Intrinsic Cellular Susceptibility to Barrett’s Esophagus in Adults Born with Esophageal Atresia

The prevalence of Barrett’s esophagus (BE) in adults born with esophageal atresia (EA) is four times higher than in the general population and presents at a younger age (34 vs. 60 years). This is (partly) a consequence of chronic gastroesophageal reflux. Given the overlap between genes and pathways involved in foregut and BE development, we hypothesized that EA patients have an intrinsic predisposition to develop BE. Transcriptomes of Esophageal biopsies of EA patients with BE (n = 19, EA/BE); EA patients without BE (n = 44, EA-only) and BE patients without EA (n = 10, BE-only) were compared by RNA expression profiling. Subsequently, we simulated a reflux episode by exposing fibroblasts of 3 EA patients and 3 controls to acidic conditions. Transcriptome responses were compared to the differential expressed transcripts in the biopsies. Predisposing single nucleotide polymorphisms, associated with BE, were slightly increased in EA/BE versus BE-only patients. RNA expression profiling and pathway enrichment analysis revealed differences in retinoic acid metabolism and downstream signaling pathways and inflammatory, stress response and oncological processes. There was a similar effect on retinoic acid signaling and immune response in EA patients upon acid exposure. These results indicate that epithelial tissue homeostasis in EA patients is more prone to acidic disturbances

Intrinsic Cellular Susceptibility to Barrett’s Esophagus in Adults Born with Esophageal Atresia

The prevalence of Barrett’s esophagus (BE) in adults born with esophageal atresia (EA) is four times higher than in the general population and presents at a younger age (34 vs. 60 years). This is (partly) a consequence of chronic gastroesophageal reflux. Given the overlap between genes and pathways involved in foregut and BE development, we hypothesized that EA patients have an intrinsic predisposition to develop BE. Transcriptomes of Esophageal biopsies of EA patients with BE (n = 19, EA/BE); EA patients without BE (n = 44, EA-only) and BE patients without EA (n = 10, BE-only) were compared by RNA expression profiling. Subsequently, we simulated a reflux episode by exposing fibroblasts of 3 EA patients and 3 controls to acidic conditions. Transcriptome responses were compared to the differential expressed transcripts in the biopsies. Predisposing single nucleotide polymorphisms, associated with BE, were slightly increased in EA/BE versus BE-only patients. RNA expression profiling and pathway enrichment analysis revealed differences in retinoic acid metabolism and downstream signaling pathways and inflammatory, stress response and oncological processes. There was a similar effect on retinoic acid signaling and immune response in EA patients upon acid exposure. These results indicate that epithelial tissue homeostasis in EA patients is more prone to acidic disturbances

Genetic prescreening of a candidate for laser refractive surgery identifies risk for inadequate tissue response: a case report

BACKGROUND: Inadequate response to corneal laser refractive surgery, e.g., ectatic corneal diseases, may not be identified by conventional examinations, hence creating therapeutic uncertainty. Herein we demonstrate the application of genetic prescreening to augment preassessment for corneal laser refractive surgery and highlight the ability to prevent the possibility of enrolling a subject at risk for developing ectatic corneal diseases. CASE PRESENTATION: Preoperative tests were performed alongside deoxyribonucleic acid (DNA) sequencing of 75 genes specific to the structure and health of the eye of a 44-year-old Caucasian male candidate for corneal laser refractive surgery. The patient had no medical, family, or psychosocial history, nor symptoms that could lead to suspect any corneal abnormalities, and conventional preoperative tests confirmed that no corneal abnormalities were present. The sequencing results uncovered rare DNA variants within the ADGRV1, PTK2, ZNF469, and KRT15 genes. These variants were considered potential risk factors for inadequate response in the patient post corneal laser refractive surgery. Subsequent reevaluation with three different last-generation corneal tomographers identified in the left eye a “warning” for a deformity of the posterior profile of the cornea. CONCLUSIONS: Genetic prescreening identifies potential risk of inadequate response to corneal laser refractive surgery where current technologies in use may lead to a hazardous predictive diagnostic uncertainty

Genetic and epigenetic changes associated with polygenic left ventricular hypertrophy

Cardiac hypertrophy (CH) is the thickening of heart muscles reducing functionality and increasing risk of cardiac disease. Commonly, pathological CH is presented as left ventricular hypertrophy (LVH) and genetic factors are known to be involved but their contribution is still poorly understood. I used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of LVH, and its control strain, the normal heart rat (NHR) to investigate genetic and epigenetic contributions to LVH independent of high blood pressure. To address this study, I used a systematic approach. Firstly, I sequenced the whole genome of HHR and NHR to identify genes related to LVH, focusing on quantitative trait locus Cm22. I found the gene for tripartite motif-containing 55 (Trim55) was significantly downregulated and also presented decreased protein expression with the presence of one exonic missense mutation that altered the protein structure. Interestingly, Trim55 mRNA expression was reduced in idiopathic dilated cardiomyopathic hearts. Secondly, I selected 42 genes previously described in monogenic forms of human cardiomyopathies and studied DNA variants, mRNA and micro RNA (miRNA) expression to determine their involvement in this polygenic model of LVH at five ages. This comprehensive approach identified the differential expression of 29 genes in at least one age group and two miRNAs in validated miRNA-mRNA interactions. These two miRNAs have binding sites for five of the genes studied. Lastly, I found circular RNA (circRNA) Hrcr was upregulated in the hypertrophic heart. I then silenced Hrcr expression in human primary cardiomyocytes to investigate its miRNA downstream targets and elucidate possible regulatory mechanisms. I described four miRNAs (miR-1-3p, miR-330, miR-27a-5p, miR-299-5p) as novel targets for HRCR and predicted 359 mRNA targets in the circRNA-miRNA-mRNA regulatory axis. In silico analysis identified 206 enriched gene ontology based on the predicted mRNA target list, including cardiomyocyte differentiation and ventricular cardiac muscle cell differentiation. The findings in this thesis suggest that 1) Trim55 is a novel functional candidate gene for polygenic LVH; 2) genes implicated in monogenic forms of cardiomyopathy may be involved in this condition and 3) circRNA expression is associated with changes in hypertrophic hearts and deserve further attention.Doctor of Philosoph

Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD