Genome-wide meta-analysis identifies novel loci conferring risk of acne vulgaris.

Acne vulgaris is a common chronic skin disorder presenting with comedones, cystic structures forming within the distal hair follicle, and in most cases additionally with inflammatory skin lesions on the face and upper torso. We performed a genome-wide association study and meta-analysis of data from 34,422 individuals with acne and 364,991 controls from three independent European-ancestry cohorts. We replicated 19 previously implicated genome-wide significant risk loci and identified four novel loci [11q12.2 (FADS2), 12q21.1 (LGR5), 17q25.3 (FASN), and 22q12.1 (ZNRF3-KREMEN1)], bringing the total number of reported acne risk loci to 50. Our meta-analysis results explain 9.4% of the phenotypic variance of acne. A polygenic model of acne risk variants showed that individuals in the top 5% of the risk percentiles had a 1.62-fold (95% CI 1.47-1.78) increased acne risk relative to individuals with average risk (20-80% on the polygenic risk score distribution). Our findings highlight the Wnt and MAPK pathways as key factors in the genetic predisposition to acne vulgaris, together with the effects of genetic variation on the structure and maintenance of the hair follicle and pilosebaceous unit. Two novel loci, 11q12.2 and 17q25.3, contain genes encoding key enzymes involved in lipid biosynthesis pathways.

Precise, Genotype-First Breast Cancer Prevention: Experience With Transferring Monogenic Findings From a Population Biobank to the Clinical Setting.

Although hereditary breast cancer screening and management are well accepted and established in clinical settings, these efforts result in the detection of only a fraction of genetic predisposition at the population level. Here, we describe our experience from a national pilot study (2018-2021) in which 180 female participants of Estonian biobank (of >150,000 participants in total) were re-contacted to discuss personalized clinical prevention measures based on their genetic predisposition defined by 11 breast cancer-related genes. Our results show that genetic risk variants are relatively common in the average-risk Estonian population. Seventy-five percent of breast cancer cases in at-risk subjects occurred before the age of 50 years. Only one-third of subjects would have been eligible for clinical screening according to the current criteria. The participants perceived the receipt of genetic risk information as valuable. Fluent cooperation of project teams supported by state-of-art data management, quality control, and secure transfer can enable the integration of research results to everyday medical practice in a highly efficient, timely, and well-accepted manner. The positive experience in this genotype-first breast cancer study confirms the value of using existing basic genomic data from population biobanks for precise prevention.

Genotype-first approach to the detection of hereditary breast and ovarian cancer risk, and effects of risk disclosure to biobank participants.

Genotype-first approach allows to systematically identify carriers of pathogenic variants in BRCA1/2 genes conferring a high risk of familial breast and ovarian cancer. Participants of the Estonian biobank have expressed support for the disclosure of clinically significant findings. With an Estonian biobank cohort, we applied a genotype-first approach, contacted carriers, and offered return of results with genetic counseling. We evaluated participants' responses to and the clinical utility of the reporting of actionable genetic findings. Twenty-two of 40 contacted carriers of 17 pathogenic BRCA1/2 variants responded and chose to receive results. Eight of these 22 participants qualified for high-risk assessment based on National Comprehensive Cancer Network criteria. Twenty of 21 counseled participants appreciated being contacted. Relatives of 10 participants underwent cascade screening. Five of 16 eligible female BRCA1/2 variant carriers chose to undergo risk-reducing surgery, and 10 adhered to surveillance recommendations over the 30-month follow-up period. We recommend the return of results to population-based biobank participants; this approach could be viewed as a model for population-wide genetic testing. The genotype-first approach permits the identification of individuals at high risk who would not be identified by application of an approach based on personal and family histories only.

Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia.

PURPOSE: Large-scale, population-based biobanks integrating health records and genomic profiles may provide a platform to identify individuals with disease-predisposing genetic variants. Here, we recall probands carrying familial hypercholesterolemia (FH)-associated variants, perform cascade screening of family members, and describe health outcomes affected by such a strategy. METHODS: The Estonian Biobank of Estonian Genome Center, University of Tartu, comprises 52,274 individuals. Among 4776 participants with exome or genome sequences, we identified 27 individuals who carried FH-associated variants in the LDLR, APOB, or PCSK9 genes. Cascade screening of 64 family members identified an additional 20 carriers of FH-associated variants. RESULTS: Via genetic counseling and clinical management of carriers, we were able to reclassify 51% of the study participants from having previously established nonspecific hypercholesterolemia to having FH and identify 32% who were completely unaware of harboring a high-risk disease-associated genetic variant. Imaging-based risk stratification targeted 86% of the variant carriers for statin treatment recommendations. CONCLUSION: Genotype-guided recall of probands and subsequent cascade screening for familial hypercholesterolemia is feasible within a population-based biobank and may facilitate more appropriate clinical management.

Exome analysis in an Estonian multiplex family with neural tube defects-a case report.

INTRODUCTION: Neural tube defects (NTDs) are a group of common and severe congenital birth defects that occur during early embryonic development due to incomplete closure of the neural tube. The genetic architecture of human NTDs, including spina bifida and hydrocephalus, is highly heterogeneous, with multiple genes/loci and both gene-gene and gene-environment interactions involved. Hence, the variation in outcomes also most likely relates to a combination of the severity of different variants in multiple genes and genetic modifiers affecting the biochemical traits. METHODS: Here, we present a multiple-spouse family with one pedigree lineage where three brothers are affected with NTDs-two lumbar spina bifidas without hydrocephalus and one obstructive hydrocephalus. We sequenced the exomes of three NTD patients and their parents. RESULTS: The analysis revealed a heterozygous c.844ins68 variant in CBS, which was carried by all affected individuals and inherited from their mother. All affected individuals had a variable set of additional low frequency deleterious variants in PTK7, PLCD4, IL4I1 or RASSF4 as likely causal loci contributing to the disease development. CONCLUSION: This report extends the current knowledge of the genetic background of NTDs and proposes that common and low frequency variants in genes involved mostly in one-carbon metabolism or planar cell polarity (PCP) pathways can act in an additive manner to increase the genetic risk of the disease.

MTHFR and MSX1 contribute to the risk of nonsyndromic cleft lip/palate.

Recent studies suggest that multiple interacting loci, with possible additional environmental factors, influence the risk for nonsyndromic oral clefts, one of the most common birth defects in humans. Advances in high-throughput genotyping technology allow the testing of multiple markers, simultaneously, in many candidate genes. We tested for associations between 176 haplotype-tagging single nucleotide polymorphisms (SNPs) in 18 candidate genes/loci and nonsyndromic clefts in a case-control study in an Estonian sample (153 patients, 205 controls). The most significant associations with nonsyndromic cleft lip with or without cleft palate (CL/P) were found for SNPs in MSX1, MTHFR, and PVRL2, including several common haplotypes in the MTHFR and MSX1 genes. The strongest association was observed for rs6446693 in the MSX1 region, which remained statistically significant after Bonferroni correction. The strongest association with nonsyndromic cleft palate (CP) was found for the SNP rs11624283 in the JAG2 gene. Epistatic interactions were observed for SNPs within PVRL2, between BCL3 and EDN1, and between IRF6 and MSX1 genes. This study provides further evidence implicating MSX1 and MTHFR in the etiology of nonsyndromic CL/P across different populations.

ROS1 Asp2213Asn polymorphism is not associated with coronary artery disease in a Greek case-control study.

BACKGROUND: Rs619203 (Cys2229Ser) and rs529038 (Asp2213Asn) polymorphisms in the ROS1 gene have been studied in relation to myocardial infarction (MI) yielding inconsistent results. We investigated the role of ROS1 rs529038 polymorphism in coronary artery disease (CAD) in Greeks using a case-control study. METHODS: Genotyping for rs529038 polymorphism was performed using a multiplex PCR technique in patients with CAD (n=294) and controls (n=311). Logistic regression analysis was used to calculate crude and adjusted odds ratios (ORs). RESULTS: Logistic regression analysis did not show any statistically significant effect of ROS1 polymorphism in the occurrence of CAD (AG vs. AA, OR: 1.08, p=0.635; GG vs. AA, OR: 0.62, p=0.220). Adjustment for confounding factors gave similar results, irrespective of the type of disease (i.e., stable coronary artery disease vs. acute coronary syndrome). CONCLUSIONS: Our findings do not support the hypothesis that ROS1 rs529038 polymorphism is an important contributing factor in the etiology of CAD in the Greek population.