CoCoRV: a rare variant analysis framework using publicly available genotype summary counts to prioritize germline disease-predisposition genes

Sequencing cases without matched healthy controls hinders prioritization of germline disease-predisposition genes. To circumvent this problem, genotype summary counts from public data sets can serve as controls. However, systematic inflation and false positives can arise if confounding factors are not addressed. We propose a new framework, consistent summary counts based rare variant burden test (CoCoRV), to address these challenges. CoCoRV has consistent variant quality control and filtering, ethnicity-stratified rare variant association test, accurate estimation of inflation factors, powerful FDR control, and can detect rare variants in high linkage disequilibrium. When we applied CoCoRV to pediatric cancer cohorts, the top genes identified were cancer-predisposition genes. We also applied CoCoRV to identify disease-predisposition genes in adult brain tumors and amyotrophic lateral sclerosis. Given that potential confounding factors were well controlled after applying the framework, CoCoRV provides a cost-effective solution to prioritizing disease-risk genes enriched with rare pathogenic variants.

Non-lesional and Lesional Lupus Skin Share Inflammatory Phenotypes that Drive Activation of CD16+ Dendritic Cells

Cutaneous lupus erythematosus (CLE) is a disfiguring and poorly understood condition frequently associated with systemic lupus. Studies to date suggest that non-lesional keratinocytes play a role in disease predisposition, but this has not been investigated in a comprehensive manner or in the context of other cell populations. To investigate CLE immunopathogenesis, normal-appearing skin, lesional skin, and circulating immune cells from lupus patients were analyzed via integrated single-cell RNA-sequencing and spatial-seq. We demonstrate that normal-appearing skin of lupus patients represents a type I interferon-rich, 'prelesional' environment that skews gene transcription in all major skin cell types and dramatically distorts cell-cell communication. Further, we show that lupus-enriched CD16+ dendritic cells undergo robust interferon education in the skin, thereby gaining pro-inflammatory phenotypes. Together, our data provide a comprehensive characterization of lesional and non-lesional skin in lupus and identify a role for skin education of CD16+ dendritic cells in CLE pathogenesis.

Commercial DNA tests and police investigations: a broad bioethical perspective

Over 30 million people worldwide have taken a commercial at-home DNA test, because they were interested in their genetic ancestry, disease predisposition or inherited traits. Yet, these consumer DNA data are also increasingly used for a very different purpose: to identify suspects in criminal investigations. By matching a suspect’s DNA with DNA from a suspect’s distant relatives who have taken a commercial at-home DNA test, law enforcement can zero in on a perpetrator. Such forensic use of consumer DNA data has been performed in over 200 criminal investigations. However, this practice of so-called investigative genetic genealogy (IGG) raises ethical concerns. In this paper, we aim to broaden the bioethical analysis on IGG by showing the limitations of an individual-based model. We discuss two concerns central in the debate: privacy and informed consent. However, we argue that IGG raises pressing ethical concerns that extend beyond these individual-focused issues. The very nature of the genetic information entails that relatives may also be affected by the individual customer’s choices. In this respect, we explore to what extent the ethical approach in the biomedical genetic context on consent and consequences for relatives can be helpful for the debate on IGG. We argue that an individual-based model has significant limitations in an IGG context. The ethical debate is further complicated by the international, transgenerational and commercial nature of IGG. We conclude that IGG should not only be approached as an individual but also—and perhaps primarily—as a collective issue.

Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis

ObjectivesTo further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for HLA-B∗27 independent associations and assessing the impact of sex on this male biased disease.MethodsHigh-confidence two-field resolution genotyping was performed on 310 cases and 2196 controls using an n-1 concordance method. Protein-coding variants were called from next-generation sequencing reads using up to four software programs and the consensus result recorded. Logistic regression tests were applied to the dataset as a whole, and also in stratified sets based on sex or HLA-B∗27 status. The amino acids driving association were also examined.ResultsTwenty-five HLA protein-coding variants were significantly associated to disease in the population. Three novel protective associations were found in a HLA-B∗27 positive population, HLA-A∗24:02 (OR = 0.4, CI = 0.2–0.7), and HLA-A amino acids Leu95 and Gln156. We identified a key set of seven loci that were common to both sexes, and robust to change in sample size. Stratifying by sex uncovered three novel risk variants restricted to the female population (HLA-DQA1∗04.01, -DQB1∗04:02, -DRB1∗08:01; OR = 2.4–3.1). We also uncovered a set of neutral variants in the female population, which in turn conferred strong effects in the male set, highlighting how population composition can lead to the masking of true associations.ConclusionPopulation stratification allowed for a nuanced investigation into the tightly linked MHC region, revealing novel HLA-B∗27 signals as well as replicating previous HLA-B∗27 dependent results. This dissection of signals may help to elucidate sex biased disease predisposition and clinical progression.

Familial Optic Disc Pits in 2 Father-Son Pairs: Clinical Features and Genetic Analysis

Congenital optic disc pits (ODPs) are well-circumscribed depressions within the optic disc. Thought to arise from anomalous closure of the optic fissure during embryonic development, they are now considered to lie on a broader spectrum of congenital optic disc anomaly (CODA). An increasing number of reports describe clustering of these cases within families, suggesting that inherited genetic elements play a role in disease predisposition. Here, we highlight the clinical features of 2 sets of father-son pairs affected with ODPs and provide preliminary molecular genetic analysis. Subjects underwent complete ophthalmological examination and imaging. In addition, whole-exome sequencing was carried out following informed consent. The resulting datasets were examined for potentially causal genetic variants, both in genes already known to be linked to CODA as well as those likely to lie in the same or similar genetic pathways. In this instance, no unambiguously causal variants were identified. This case series highlights the familial inheritance of ODPs, adding to the existing body of literature supporting an underlying genetic cause for this rare clinical entity. The inclusion here of specific molecular findings raises the hope that the genetic pathophysiology underlying rare entities like ODPs might be clarified in the future by the addition of similarly molecular-documented reports.

Ancestrally and Temporally Diverse Analysis of Penetrance of Clinical Variants in 72,434 Individuals

ABSTRACTA major goal of genomic medicine is to quantify the disease risk of genetic variants. Here, we report the penetrance of 37,772 clinically relevant variants (including those reported in ClinVar1 and of loss-of-function consequence) for 197 diseases in an analysis of exome sequence data for 72,434 individuals over five ancestries and six decades of ages from two large-scale population-based biobanks (BioMe Biobank and UK Biobank). With a high-quality set of 5,359 clinically impactful variants, we evaluate disease prevalence in carriers and non-carriers to interrogate major determinants and implications of penetrance. First, we associate biomarker levels with penetrance of variants in known disease-predisposition genes and illustrate their clear biological link to disease. We then systematically uncover large numbers of ClinVar pathogenic variants that confer low risk of disease, even among those reviewed by experts, while delineating stark differences in variant penetrance by molecular consequence. Furthermore, we ascertain numerous variants present in non-European ancestries and reveal how increasing carrier age modifies penetrance estimates. Lastly, we examine substantial heterogeneity of penetrance among variants in known disease-predisposition genes for conditions such as familial hypercholesterolemia and breast cancer. These data indicate that existing categorical systems for variant classification do not adequately capture disease risk and warrant consideration of a more quantitative system based on population-based penetrance to evaluate clinical impact.

Protective role of ERCC4 SNP rs1800067 Minor Allele in Gallbladder Carcinogenesis.

Purpose: Gallbladder cancer (GBC) is the most aggressive tumor of the biliary tract. Since DNA damage is one of the common events in GBC, we hypothesized that nucleotide excision repair enzymes may be defective in GBC. We aimed to investigate the association of SNP rs1800067 (G/A) of ERCC4 with the disease predisposition in gallbladder cancer and its prognosis. We have also investigated the expression of ERCC4 in GBC patients and gallstone patients for any possible correlation with the SNP.Methods: In 350 GBC patients and 300 controls, ERCC4 SNP rs1800067 was genotyped by PCR-RFLP. Semi-quantitative RT-PCR was performed using ERCC4 and internal control β-actin primers in gallstone and tumor biopsy. We adopted the Kaplan-Meier plot and log-rank tests to explore the association of rs1800067 and prognosis of gallbladder cancer patients. Results: We demonstrate that the minor allele A is less frequent in GBC patients than healthy controls, suggesting the association of GA genotype with decreased risk of GBC. rs1800067 genotypes have significantly differential frequencies relative to clinical parameters. The relative expression of ERCC4 is significantly differentially expressed among early and late stages of tumors. Patients with combined GA+AA genotypes had longer overall survival in patients with early stages of tumors and with chemotherapy.Conclusion: Our results suggest that minor allele A is significantly associated with reduced risk of gallbladder carcinogenesis. The upregulation of relative mRNA expression of ERCC4 is an early event in the progression of gallbladder cancer.

Highly diversified core promoters in the human genome and their effects on gene expression and disease predisposition

Background Core promoter controls transcription initiation. However, little is known for core promoter diversity in the human genome and its relationship with diseases. We hypothesized that as a functional important component in the genome, the core promoter in the human genome could be under evolutionary selection, as reflected by its highly diversification in order to adjust gene expression for better adaptation to the different environment. Results Applying the “Exome-based Variant Detection in Core-promoters” method, we analyzed human core-promoter diversity by using the 2682 exome data sets of 25 worldwide human populations sequenced by the 1000 Genome Project. Collectively, we identified 31,996 variants in the core promoter region (− 100 to + 100) of 12,509 human genes (https://dbhcpd.fhs.um.edu.mo). Analyzing the rich variation data identified highly ethnic-specific patterns of core promoter variation between different ethnic populations, the genes with highly variable core promoters, the motifs affected by the variants, and their involved functional pathways. eQTL test revealed that 12% of core promoter variants can significantly alter gene expression level. Comparison with GWAS data we located 163 variants as the GWAS identified traits associated with multiple diseases, half of these variants can alter gene expression. Conclusion Data from our study reals the highly diversified nature of core promoter in the human genome, and highlights that core promoter variation could play important roles not only in gene expression regulation but also in disease predisposition.

The Chemical Exposome of Human Aging

Aging is an inevitable biological phenomenon displayed by single cells and organs to entire organismal systems. Aging as a biological process is characterized as a progressive decline in intrinsic biological function. Understanding the causative mechanisms of aging has always captured the imagination of researchers since time immemorial. Although both biological and chronological aging are well defined and studied in terms of genetic, epigenetic, and lifestyle predispositions, the hallmarks of aging in terms of small molecules (i.e., endogenous metabolites to chemical exposures) are limited to obscure. On top of the endogenous metabolites leading to the onset and progression of healthy aging, human beings are constantly exposed to a natural and anthropogenic “chemical” environment round the clock, from conception till death, affecting one’s physiology, health and well-being, and disease predisposition. The research community has started gaining sizeable insights into deciphering the aging factors such as immunosenescence, nutrition, frailty, inflamm-aging, and diseases till date, without much input from their interaction with exogenous chemical exposures. The “exposome” around us, mostly, accelerates the process of aging by affecting the internal biological pathways and signaling mechanisms that result in the deterioration of human health. However, the entirety of exposome on human aging is far from established. This review intends to catalog the known and established associations of the exposome from past studies focusing on aging in humans and other model organisms. Further discussed are the current technologies and informatics tools that enable the study of aging exposotypes, and thus, provide a window of opportunities and challenges to study the “aging exposome” in granular details.