Role Of Rare Variants Research Articles

Rare Mutations in CCDC7 Contribute to Early-Onset Preeclampsia by Inhibiting Trophoblast Migration and Invasion.

Rare gene variants have been found to play a role in complex disorders. Preeclampsia, and especially early-onset preeclampsia, has a strong genetic link. However, the role of rare variants in the offspring of mothers with preeclampsia remains unclear. In this study, whole-exome sequencing (WES) was used to identify rare pathogenic variants in two families with early-onset preeclampsia. Two heterozygous rare variants in CCDC7, c.625C>T (p.R209C) and c.1015C>T (p.R339X), were detected in two families and were cosegregated in the offspring of preeclamptic pregnancies. We examined the spatiotemporal expression pattern of CCDC7 in human placental villi and the effects of CCDC7 on migration and invasion of trophoblast cells JEG-3. The quantitative real-time PCR and Western blot results showed that the expression of CCDC7 in placental villi was the lowest during the first trimester and increased as the pregnancy progressed. The CCDC7 p.R339X variant showed a decrease in mRNA and protein expressions. Loss-of-function assays showed that knockdown of CCDC7 suppressed the migration and invasion of JEG-3 cells. In conclusion, CCDC7 is a potential susceptibility gene for preeclampsia, which is key for the migration and invasion of trophoblast cells. Rare variants of preeclampsia in offspring may play a crucial role in the pathogenesis of preeclampsia and require further research.

Rare variant associations with plasma protein levels in the UK Biobank

Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers and discover drug targets1–4. Because previous proteogenomic studies have focused on common variation via genome-wide association studies, the contribution of rare variants to the plasma proteome remains largely unknown. Here we identify associations between rare protein-coding variants and 2,923 plasma protein abundances measured in 49,736 UK Biobank individuals. Our variant-level exome-wide association study identified 5,433 rare genotype–protein associations, of which 81% were undetected in a previous genome-wide association study of the same cohort5. We then looked at aggregate signals using gene-level collapsing analysis, which revealed 1,962 gene–protein associations. Of the 691 gene-level signals from protein-truncating variants, 99.4% were associated with decreased protein levels. STAB1 and STAB2, encoding scavenger receptors involved in plasma protein clearance, emerged as pleiotropic loci, with 77 and 41 protein associations, respectively. We demonstrate the utility of our publicly accessible resource through several applications. These include detailing an allelic series in NLRC4, identifying potential biomarkers for a fatty liver disease-associated variant in HSD17B13 and bolstering phenome-wide association studies by integrating protein quantitative trait loci with protein-truncating variants in collapsing analyses. Finally, we uncover distinct proteomic consequences of clonal haematopoiesis (CH), including an association between TET2-CH and increased FLT3 levels. Our results highlight a considerable role for rare variation in plasma protein abundance and the value of proteogenomics in therapeutic discovery.

Targeted next-generation sequencing for genetic variants of left ventricular mass status among community-based adults in Taiwan.

Background: Left ventricular mass is a highly heritable disease. Previous studies have suggested common genetic variants to be associated with left ventricular mass; however, the roles of rare variants are still unknown. We performed targeted next-generation sequencing using the TruSight Cardio panel, which provides comprehensive coverage of 175 genes with known associations to 17 inherited cardiac conditions. Methods: We conducted next-generation sequencing using the Illumina TruSight Cardiomyopathy Target Genes platform using the 5% and 95% extreme values of left ventricular mass from community-based participants. After removing poor-quality next-generation sequencing subjects, including call rate <98% and Mendelian errors, 144 participants were used for the analysis. We performed downstream analysis, including quality control, alignment, coverage length, and annotation; after setting filtering criteria for depths more than 60, we found a total of 144 samples and 165 target genes for further analysis. Results: Of the 12,287 autosomal variants, most had minor allele frequencies of <1% (rare frequency), and variants had minor allele frequencies ranging from 1% to 5%. In the multi-allele variant analyses, 16 loci in 15 genes were significant using the false discovery rate of less than .1. In addition, gene-based analyses using continuous and binary outcomes showed that three genes (CASQ2, COL5A1, and FXN) remained to be associated with left ventricular mass status. One single-nucleotide polymorphism (rs7538337) was enriched for the CASQ2 gene expressed in aorta artery (p = 4.6 × 10-18), as was another single-nucleotide polymorphism (rs11103536) for the COL5A1 gene expressed in aorta artery (p = 2.0 × 10-9). Among the novel genes discovered, CASQ2, COL5A1, and FXN are within a protein-protein interaction network with known cardiovascular genes. Conclusion: We clearly demonstrated candidate genes to be associated with left ventricular mass. Further studies to characterize the target genes and variants for their functional mechanisms are warranted.

Rare Variants in Systemic Lupus Erythematosus: From Monogenic to Polygenic Disease

The clinical and genotypic characterization of autoimmune diseases, including systemic lupus erythematosus (SLE), has made great strides recently as a result of tremendous advancements in gene sequencing technologies. Systemic lupus erythematosus is a complex multisystem disease characterized by high clinical variability due to abnormalities in both the innate and adaptive immune systems. Several genetic variants as well as environmental and hormonal factors have been identified, but the etiology of lupus is not fully understood yet. The ability of genome-wide association studies to scan thousands of individuals has enabled researchers to associate thousands of common variants to lupus. Common polymorphisms may jointly predispose to lupus, but their individual impact on the disease is minimal. It's becoming progressively more evident that rare mutations have a far higher influence. The role of rare variation in lupus has been the subject of intense research. Several approaches including genotyped-based follow-up of the variants in families, hierarchical screening, and imputation, have been applied to elucidate their functional involvement. Nevertheless, due to their rarity and the absence of standardized methodology, rare variants are still challenging to study. Most lupus patients present a polygenic form of the disease, which is defined by the complex interplay between genetic and environmental factors. Still, certain lupus patients and patients with lupus-like phenotypes might be affected by monogenic lupus, a group of disorders largely caused by individual gene mutation abnormalities. Although monogenic lupus is rare, it has been associated with a sizable number of genes in a range of pathways, mostly resulting in early-onset phenotypes. The study of rare variants causing monogenic lupus has resulted in incredibly useful breakthroughs in our understanding of the function of rare variants in the disease, nonetheless further research is still required.

Whole-exome sequencing in a Japanese multiplex family identifies new susceptibility genes for intracranial aneurysms.

Intracranial aneurysms (IAs) cause subarachnoid hemorrhage, which has high rates of mortality and morbidity when ruptured. Recently, the role of rare variants in the genetic background of complex diseases has been increasingly recognized. The aim of this study was to identify rare variants for susceptibility to IA. Whole-exome sequencing was performed on seven members of a Japanese pedigree with highly aggregated IA. Candidate genes harboring co-segregating rare variants with IA were re-sequenced and tested for association with IA using additional 500 probands and 323 non-IA controls. Functional analysis of rare variants detected in the pedigree was also conducted. We identified two gene variants shared among all four affected participants in the pedigree. One was the splicing donor c.1515+1G>A variant in NPNT (Nephronectin), which was confirmed to cause aberrant splicing by a minigene assay. The other was the missense p.P83T variant in CBY2 (Chibby family member 2). Overexpression of p.P83T CBY2 fused with red fluorescent protein tended to aggregate in the cytoplasm. Although Nephronectin has been previously reported to be involved in endothelial angiogenic functions, CBY2 is a novel molecule in terms of vascular pathophysiology. We confirmed that CBY2 was expressed in cerebrovascular smooth muscle cells in an isoform2-specific manner. Targeted CBY2 re-sequencing in additional case-control samples identified three deleterious rare variants (p.R46H, p.P83T, and p.L183R) in seven probands, showing a significant enrichment in the overall probands (8/501) compared to the controls (0/323) (p = 0.026, Fisher's extract test). NPNT and CBY2 were identified as novel susceptibility genes for IA. The highly heterogeneous and polygenic architecture of IA susceptibility can be uncovered by accumulating extensive analyses that focus on each pedigree with a high incidence of IA.

Rare variants in previously identified linkage regions associated with carotid plaque in Dominican Republic families.

Carotid plaque is a subclinical measure of atherosclerosis. We have previously shown measures of carotid plaque to be heritable in a sample of 100 Dominican families and found evidence for linkage and association of common variants (CVs) on 7q36, 11p15, 14q32 and 15q23 with plaque presence. Our current study aimed to refine these regions further and identify rare variants (RVs) influencing plaque presence. Therefore, we performed targeted sequencing of the one LOD unit down region on 7q36, 11p15, 14q32 and 15q23 in 12 Dominican families with evidence for linkage to plaque presence. Gene-based RV analyses were performed using the Sequence Association Test for familial data (F-SKAT) under two filtering algorithms; 1. all exonic RVs and 2. non-synonymous RVs. Replication analyses were performed using a sample of 22 Dominican families and 556 unrelated Dominicans with Exome Array data. To identify additional non-synonymous RVs influencing plaque, we looked for co-segregation of RVs with plaque in each of the sequenced families. Our most strongly associated gene with evidence for replication was AMPD3 which showed suggestive association with plaque presence in the sequenced families (exonic RV p = 0.003, nonsynonymous RV p = 0.005) and replication families (exonic RV p = 0.04, nonsynonymous RV p = 0.02). Examination of the sequenced family pedigrees revealed two missense variants on chromosome 11 which co-segregated with plaque presence in one of our families; rs61751342 (located in DENND2B), and rs61760882 (located in RNF141). The rs61751342 missense variant is an eQTL for SCUBE2 in the atrial appendage. Notably, SCUBE2 encodes a protein which interacts with vascular endothelial growth factor (VEGF) receptor 2 to regulate VEGF-induced angiogenesis, thus providing biologic plausibility for this gene in atherosclerosis. In conclusion, using targeted sequencing of previously-identified linkage regions, we have identified suggestive evidence for the role of RVs in carotid plaque pathogenesis.

Cohort Analysis of 67 Charcot-Marie-Tooth Italian Patients: Identification of New Mutations and Broadening of Phenotype Expression Produced by Rare Variants.

Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited motor sensory neuropathy, which clusters a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with different phenotypes. The goal of this study is to identify the genetic features in the recruited cohort of patients, highlighting the role of rare variants in the genotype-phenotype correlation. We enrolled 67 patients and applied a diagnostic protocol including multiple ligation-dependent probe amplification for copy number variation (CNV) detection of PMP22 locus, and next-generation sequencing (NGS) for sequencing of 47 genes known to be associated with CMT and routinely screened in medical genetics. This approach allowed the identification of 26 patients carrying a whole gene CNV of PMP22. In the remaining 41 patients, NGS identified the causative variants in eight patients in the genes HSPB1, MFN2, KIF1A, GDAP1, MTMR2, SH3TC2, KIF5A, and MPZ (five new vs. three previously reported variants; three sporadic vs. five familial variants). Familial segregation analysis allowed to correctly interpret two variants, initially reported as “variants of uncertain significance” but re-classified as pathological. In this cohort is reported a patient carrying a novel familial mutation in the tail domain of KIF5A [a protein domain previously associated with familial amyotrophic lateral sclerosis (ALS)], and a CMT patient carrying a HSPB1 mutation, previously reported in ALS. These data indicate that combined tools for gene association in medical genetics allow dissecting unexpected phenotypes associated with previously known or unknown genotypes, thus broadening the phenotype expression produced by either pathogenic or undefined variants.Clinical trial registration: ClinicalTrials.gov (NCT03084224).

The Role of Pharmacogenetics in Smoking.

Smoking continues to be the leading preventable contributor to death worldwide. Twin studies have suggested a significant genetic contribution underlying most smoking behaviors (40-70% heritability estimates). Candidate gene studies of smoking phenotypes have identified several pharmacogenes implicated in nicotine's pharmacokinetics (CYP2A6, CYP2B6, CYP2A13, FMOs, UGTs, and OCT2), and nicotine's pharmacodynamic response in the central nervous system (nicotinic acetylcholine receptors, as well as through the dopaminergic and serotonergic systems). Subsequent genome-wide association studies (GWAS) have confirmed the role of certain pharmacogenes through hypothesis-free approaches. Furthermore, pharmacogenes that alter the efficacy of smoking cessation pharmacotherapies, including nicotine replacement therapies, bupropion, and varenicline, may also impact quitting success. In this brief review we highlight the role of pharmacogenes in smoking behaviors, such as smoking status, consumption, nicotine dependence, spontaneous quitting, and altered abstinence to pharmacotherapies; We provide examples from initial candidate gene associations and subsequent GWAS. The genes CYP2A6 and the CHRNA5-A3-B4 confer the most replicated sources of genetic variation in smoking behaviors, likely due to their importance in nicotine's pharmacology. We will also provide examples of genetic scoring approaches, and the role of rare variants in explaining a portion of the missing heritability in smoking behaviors.

Role of Rare Variants in Craniofacial Enhancer Regions in the Etiology of Non‐Syndromic Orofacial Clefts

Background Orofacial clefts are the most common congenital birth defects accounting for 65% of all head and neck deformities. To date, Genome Wide Association Studies (GWAS) have identified over 60 common risk loci for Non syndromic orofacial clefts (NSOFCs). Collectively, these loci only explain 20-30% of its heritability. Interestingly, a substantial number of these loci are in the non-coding regulatory elements of the genome. Thus, to provide more explanation for the “missing heritability”, we investigated putative craniofacial and ectodermal enhancer elements for rare variants with probable etiological implication in the pathogenesis of NSOFCs. Methods Candidate craniofacial enhancer elements were identified from previous literatures and mouse models. Following filtration to include only those with more than one rare (MAF < 1%) SNP from our data. The final test datasets included 73 regions, which consisted of 168 unique SNPs. Two different burden tests (combined multivariate and collapsing (CMC) test and sequence kernel association test (SKAT) were performed. Results We found a suggestive significant association (p = 0.009) with a putative craniofacial enhancer located within an intronic region of PRDM16 gene (Chr1:3148388-3149216) after correcting for multiple testing. PRDM16 is a known cleft candidate gene and analysis is on-going to determine the enhancer activity of this region using ATAC-Seq data from relevant craniofacial tissues. Conclusion Our findings suggest a role for rare variants within craniofacial enhancer regions in the complex etiology of NSOFCs.

Genetic contributions to bipolar disorder: current status and future directions.

Bipolar disorder (BD) is a highly heritable mental disorder and is estimated to affect about 50 million people worldwide. Our understanding of the genetic etiology of BD has greatly increased in recent years with advances in technology and methodology as well as the adoption of international consortiums and large population-based biobanks. It is clear that BD is also highly heterogeneous and polygenic and shows substantial genetic overlap with other psychiatric disorders. Genetic studies of BD suggest that the number of associated loci is expected to substantially increase in larger future studies and with it, improved genetic prediction of the disorder. Still, a number of challenges remain to fully characterize the genetic architecture of BD. First among these is the need to incorporate ancestrally-diverse samples to move research away from a Eurocentric bias that has the potential to exacerbate health disparities already seen in BD. Furthermore, incorporation of population biobanks, registry data, and electronic health records will be required to increase the sample size necessary for continued genetic discovery, while increased deep phenotyping is necessary to elucidate subtypes within BD. Lastly, the role of rare variation in BD remains to be determined. Meeting these challenges will enable improved identification of causal variants for the disorder and also allow for equitable future clinical applications of both genetic risk prediction and therapeutic interventions.

Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants

BackgroundOtitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility.MethodsWe...

An update on the genetics of systemic lupus erythematosus.

The aim of this study is to update on the most recent findings on the genetics of systemic lupus erythematosus. Our overview focuses particularly on results from expression quantitative trait loci, exome sequencing, and rare variants and their impact on disease. Systemic lupus erythematosus is a systemic autoimmune disease for which a significant number of susceptibility genes have been identified. Several genome-wide association studies were recently published in different populations that provide a better picture of the molecular mechanisms. It is becoming clear that the genetic architecture of lupus is quite well established but more information is required on the role of rare variants.

Population genetic simulation study of power in association testing across genetic architectures and study designs.

While it is well established that genetics can be a major contributor to population variation of complex traits, the relative contributions of rare and common variants to phenotypic variation remains a matter of considerable debate. Here, we simulate genetic and phenotypic data across different case/control panel sampling strategies, sequencing methods, and genetic architecture models based on evolutionary forces to determine the statistical performance of rare variant association tests (RVATs) widely in use. We find that the highest statistical power of RVATs is achieved by sampling case/control individuals from the extremes of an underlying quantitative trait distribution. We also demonstrate that the use of genotyping arrays, in conjunction with imputation from a whole‐genome sequenced (WGS) reference panel, recovers the vast majority (90%) of the power that could be achieved by sequencing the case/control panel using current tools. Finally, we show that for dichotomous traits, the statistical performance of RVATs decreases as rare variants become more important in the trait architecture. Our results extend previous work to show that RVATs are insufficiently powered to make generalizable conclusions about the role of rare variants in dichotomous complex traits.

A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular,RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.

Su1069 – The Role of Rare Variants in Muc4 in Gastric Cancer Susceptibility in Gastric Cancer Family

Su1069 – The Role of Rare Variants in Muc4 in Gastric Cancer Susceptibility in Gastric Cancer Family

Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10−8; APOC3 and triglyceride levels, P = 1.5 × 10−26), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10−8), indicating a role for this gene in lipid metabolism.

Functional Connectivity and Genetic Profile of a "Double-Cortex"-Like Malformation.

Laminar heterotopia is a rare condition consisting in an extra layer of gray matter under properly migrated cortex; it configures an atypical presentation of periventricular nodular heterotopia (PNH) or a double cortex (DC) syndrome. We conducted an original functional MRI (fMRI) analysis in a drug-resistant epilepsy patient with “double-cortex”-like malformation to reveal her functional connectivity (FC) as well as a wide genetic analysis to identify possible genetic substrates. Heterotopias were segmented into region of interests (ROIs), whose voxel-wise FC was compared to that of (i) its normally migrated counterpart, (ii) its contralateral homologous, and (iii) those of 30 age-matched healthy controls. Extensive genetic analysis was conducted to screen cortical malformations-associated genes. Compared to healthy controls, both laminar heterotopias and the overlying cortex showed significant reduction of FC with the contralateral hemisphere. Two heterozygous variants of uncertain clinical significance were found, involving autosomal recessive disease-causing genes, FAT4 and COL18A1. This first FC analysis of a unique case of “double-cortex”-like malformation revealed a hemispheric connectivity segregation both in the laminar cortex as in the correctly migrated one, with a new pattern of genes’ mutations. Our study suggests the altered FC could have an electrophysiological and functional impact on large-scale brain networks, and the involvement of not yet identified genes in “double-cortex”-like malformation with a possible role of rare variants in recessive genes as pathogenic cofactors.

Abstract MP62: Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

Introduction: Alcohol intake modifies plasma lipid levels and such effects may be modulated by genetic variants. We use emerging statistical methods that extend well-established common variant approaches to characterize the role of aggregated rare and low-frequency variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. Methods: Up to 247,870 exonic variants on the Illumina HumanExome BeadChip and fasting plasma triglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL-c and LDL-c) were measured in 46,443 European Americans from 4 studies (the Atherosclerosis Risk in Communities (ARIC) study, the Framingham Heart Study, the Netherlands Epidemiology of Obesity Study and the Women’s Genome Health Study) of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Using the gene-based rareGE method, we conducted exome-wide gene-environment (GxE) tests with genetic main effects estimated as fixed and random effects, and a joint analysis of genetic main and GxE interaction effects. Rare and low-frequency (minor allele frequency ≤ 5%) functional variants, (i.e. frameshift, nonsynonymous, stop/gain, stop/loss, and splicing) were aggregated by genes. Two dichotomous self-reported alcohol consumption variables, current drinker (at least 1 drink per week, yes/no) and regular drinker (at least 2 drinks per week, yes/no) were considered. A sample size weighted Z-test (weighted Stouffer’s method) was used to meta-analyze study-specific p -values. Exome-wide significance level was set at p &lt; 3.7*10 -6 (0.05/13368 genes), using a Bonferroni procedure to correct for multiple testing. Results: We identified 24 gene-lipid associations at 13 known lipid loci (within 500kb) harboring rare and low-frequency variants through the joint analysis. In ARIC, numerous genes ( PCSK9, LPL, LIPG, ANGPTL4, APOB, APOC3-A5 ) remained significant after conditioning on common index single nucleotide polymorphisms (SNPs), suggesting an independent role for rare variants at loci highlighted by previous genome-wide association studies. However, no significant gene-alcohol interactions were observed with rare and low-frequency variants on TG, HDL-c or LDL-c. Conclusion: This study applied new statistical approaches to investigate the role of rare and low-frequency variants in gene-alcohol consumption interactions on lipid levels. Results show promise for other larger scale studies analyzing rare variant GxE interactions.

Evaluating the breast cancer predisposition role of rare variants in genes associated with low-penetrance breast cancer risk SNPs

BackgroundGenome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with small increases in breast cancer risk. Studies to date suggest that some SNPs alter the expression of the associated genes, which potentially mediates risk modification. On this basis, we hypothesised that some of these genes may be enriched for rare coding variants associated with a higher breast cancer risk.MethodsThe coding regions and exon-intron boundaries of 56 genes that have either been proposed by GWASs to be the regulatory targets of the SNPs and/or located < 500 kb from the risk SNPs were sequenced in index cases from 1043 familial breast cancer families that previously had negative test results for BRCA1 and BRCA2 mutations and 944 population-matched cancer-free control participants from an Australian population. Rare (minor allele frequency ≤ 0.001 in the Exome Aggregation Consortium and Exome Variant Server databases) loss-of-function (LoF) and missense variants were studied.ResultsLoF variants were rare in both the cases and control participants across all the candidate genes, with only 38 different LoF variants observed in a total of 39 carriers. For the majority of genes (n = 36), no LoF variants were detected in either the case or control cohorts. No individual gene showed a significant excess of LoF or missense variants in the cases compared with control participants. Among all candidate genes as a group, the total number of carriers with LoF variants was higher in the cases than in the control participants (26 cases and 13 control participants), as was the total number of carriers with missense variants (406 versus 353), but neither reached statistical significance (p = 0.077 and p = 0.512, respectively). The genes contributing most of the excess of LoF variants in the cases included TET2, NRIP1, RAD51B and SNX32 (12 cases versus 2 control participants), whereas ZNF283 and CASP8 contributed largely to the excess of missense variants (25 cases versus 8 control participants).ConclusionsOur data suggest that rare LoF and missense variants in genes associated with low-penetrance breast cancer risk SNPs may contribute some additional risk, but as a group these genes are unlikely to be major contributors to breast cancer heritability.

KL 39 Update on genetics in preeclampsia

Pre-eclampsia is a key challenge in all levels of obstetric care, because the onset and clinical course is unpredictable. The public health impact of pre-eclampsia is not limited to the obstetric and pediatric domains. It is also associated with increased risk of cardiovascular diseases in later life of the mother and the offspring. Pre-eclampsia has its origins in early pregnancy long before the onset of clinical disease. Risk prediction tools, including sequence variants, to predict pre-eclampsia and its subgroups in early pregnancy would be a major advance in healthcare. The use of genetic profiling has the advantage of being a primary factor, unchanged by pregnancy or disease processes. The contribution of maternal and fetal (paternal) genotypes needs to be taken into consideration. The InterPregGen study has assembled a consortium of researchers from Europe, Central Asia and South America with the aim of identifying sequence variants in the genome of mothers and/or offspring affected by pre-eclampsia. The consortium has reported the discovery of the first genome-wide significant susceptibility locus in the offspring from pre-eclamptic pregnancies. The locus is near the fms-related tyrosine kinase gene(FLT1) encoding fms-like tyrosine kinase 1 implicated in pre-eclampsia. There might be advantages for studying the role of rare variation in pre-eclampsia in founder populations. Genotype-phenotype relationships can be further studied combining genetic data and health data from population registries. In a targeted exome sequencing study we have found maternal low-frequency variants in FLT1 that may protect from pre-eclampsia. These variants are enriched in a Finnish population and may also protect from heart failure in later life. Any new gene discovery will highlight a known pathway or reveal a new biochemical pathway in the pathogenic process leading to pre-eclampsia and may also help identifying individuals with higher risk for later cardiovascular disease.