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JAMA Network Open May 2024Polygenic embryo screening (PES) is a novel technology that estimates the likelihood of developing future conditions (eg, diabetes or depression) and traits (eg, height...
IMPORTANCE
Polygenic embryo screening (PES) is a novel technology that estimates the likelihood of developing future conditions (eg, diabetes or depression) and traits (eg, height or cognitive ability) in human embryos, with the goal of selecting which embryos to use. Given its commercial availability and concerns raised by researchers, clinicians, bioethicists, and professional organizations, it is essential to inform key stakeholders and relevant policymakers about the public's perspectives on this technology.
OBJECTIVE
To survey US adults to examine general attitudes, interests, and concerns regarding PES use.
DESIGN, SETTING, AND PARTICIPANTS
For this survey study, data were collected from 1 stratified sample and 1 nonprobability sample (samples 1 and 2, respectively) between March and July 2023. The surveys measured approval, interest, and concerns regarding various applications of PES. In the second sample, presentation of a list of potential concerns was randomized (presented at survey onset vs survey end). The survey was designed using Qualtrics and distributed to participants through Prolific, an online sampling firm. Sample 1 was nationally representative with respect to gender, age, and race and ethnicity; sample 2 was recruited without specific demographic criteria. Analyses were conducted between March 2023 and February 2024.
MAIN OUTCOMES AND MEASURES
Participants reported their approval, interest, and concerns regarding various applications of PES and outcomes screened (eg, traits and conditions). Statistical analysis was conducted using independent samples t tests and repeated-measures analyses of variance.
RESULTS
Of the 1435 respondents in sample 1, demographic data were available for 1427 (mean [SD] age, 45.8 [16.0] years; 724 women [50.7%]). Among these 1427 sample 1 respondents, 1027 (72.0%) expressed approval for PES and 1169 (81.9%) expressed some interest in using PES if already undergoing in vitro fertilization (IVF). Approval among these respondents for using PES for embryo selection was notably high for physical health conditions (1109 [77.7%]) and psychiatric health conditions (1028 [72.0%]). In contrast, there was minority approval for embryo selection based on PES for behavioral traits (514 [36.0%]) and physical traits (432 [30.3%]). Nevertheless, concerns about PES leading to false expectations and promoting eugenic practices were pronounced, with 787 of 1422 (55.3%) and 780 of 1423 (54.8%) respondents finding them very to extremely concerning, respectively. Sample 2 included 192 respondents (mean [SD] age 37.7 [12.2] years; 110 men [57.3%]). These respondents were presented concerns at survey onset (n = 95) vs survey end (n = 97), which was associated with less approval (28-percentage point decrease) and more uncertainty (24 percentage-point increase) but with only slightly higher disapproval (4 percentage-point increase).
CONCLUSIONS AND RELEVANCE
These findings suggest that it is critical for health care professionals and medical societies to consider and understand the perspectives of diverse stakeholders (eg, patients undergoing IVF, clinicians, and the general public), given the absence of regulation and the recent commercial availability of PES.
Topics: Humans; Female; Adult; Male; Public Opinion; Middle Aged; Surveys and Questionnaires; United States; Multifactorial Inheritance; Genetic Testing
PubMed: 38743425
DOI: 10.1001/jamanetworkopen.2024.10832 -
Nucleic Acids Research Jan 2024To fully unlock the potential of pigs as both agricultural species for animal-based protein food and biomedical models for human biology and disease, a comprehensive...
To fully unlock the potential of pigs as both agricultural species for animal-based protein food and biomedical models for human biology and disease, a comprehensive understanding of molecular and cellular mechanisms underlying various complex phenotypes in pigs and how the findings can be translated to other species, especially humans, are urgently needed. Here, within the Farm animal Genotype-Tissue Expression (FarmGTEx) project, we build the PigBiobank (http://pigbiobank.farmgtex.org) to systematically investigate the relationships among genomic variants, regulatory elements, genes, molecular networks, tissues and complex traits in pigs. This first version of the PigBiobank curates 71 885 pigs with both genotypes and phenotypes from over 100 pig breeds worldwide, covering 264 distinct complex traits. The PigBiobank has the following functions: (i) imputed sequence-based genotype-phenotype associations via a standardized and uniform pipeline, (ii) molecular and cellular mechanisms underlying trait-associations via integrating multi-omics data, (iii) cross-species gene mapping of complex traits via transcriptome-wide association studies, and (iv) high-quality results display and visualization. The PigBiobank will be updated timely with the development of the FarmGTEx-PigGTEx project, serving as an open-access and easy-to-use resource for genetically and biologically dissecting complex traits in pigs and translating the findings to other species.
Topics: Animals; Genome-Wide Association Study; Genotype; Multifactorial Inheritance; Phenotype; Swine; Databases, Genetic; Multiomics
PubMed: 37956339
DOI: 10.1093/nar/gkad1080 -
Kidney International Apr 2024Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been...
Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knockout mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knockout of Foxd2 in ureteric bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift toward a stromal cell identity. Histology of Foxd2 knockout mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases.
Topics: Adult; Animals; Humans; Mice; Embryonic Structures; Genome-Wide Association Study; Kidney; Kidney Diseases; Mice, Knockout; Nephrons; Transcription Factors; Urinary Tract; Urogenital Abnormalities; Vesico-Ureteral Reflux; Forkhead Transcription Factors
PubMed: 38154558
DOI: 10.1016/j.kint.2023.11.032 -
Cancer Epidemiology, Biomarkers &... Nov 2023Polygenic risk scores (PRS) summarize an individual's germline genetic risk, but it is unclear whether PRS offer independent information for pancreatic cancer risk... (Review)
Review
BACKGROUND
Polygenic risk scores (PRS) summarize an individual's germline genetic risk, but it is unclear whether PRS offer independent information for pancreatic cancer risk prediction beyond routine clinical data.
METHODS
We searched 8 databases from database inception to March 10, 2023 to identify studies evaluating the independent performance of pancreatic cancer-specific PRS for pancreatic cancer beyond clinical risk factors.
RESULTS
Twenty-one studies examined associations between a pancreatic cancer-specific PRS and pancreatic cancer. Seven studies evaluated risk factors beyond age and sex. Three studies evaluated the change in discrimination associated with the addition of PRS to routine risk factors and reported improvements (AUCs: 0.715 to 0.745; AUC 0.791 to 0.830; AUC from 0.694 to 0.711). Limitations to clinical applicability included using source populations younger/healthier than those at risk for pancreatic cancer (n = 10), exclusively of European ancestry (n = 13), or controls without relevant exposures (n = 1).
CONCLUSIONS
While most studies of pancreatic cancer-specific PRS did not evaluate the independent discrimination of PRS for pancreatic cancer beyond routine risk factors, three that did showed improvements in discrimination.
IMPACT
For pancreatic cancer PRS to be clinically useful, they must demonstrate substantial improvements in discrimination beyond established risk factors, apply to diverse ancestral populations representative of those at risk for pancreatic cancer, and use appropriate controls.
Topics: Humans; Genetic Predisposition to Disease; Risk Factors; Databases, Factual; Multifactorial Inheritance; Genome-Wide Association Study; Pancreatic Neoplasms
PubMed: 37610426
DOI: 10.1158/1055-9965.EPI-23-0468 -
A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.Hepatology Communications Jun 2024Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We...
BACKGROUND
Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis.
METHODS
Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239).
RESULTS
A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis.
CONCLUSIONS
PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.
Topics: Humans; Polymorphism, Single Nucleotide; Liver Cirrhosis, Alcoholic; Male; Female; Middle Aged; Genome-Wide Association Study; White People; Multifactorial Inheritance; Aged; Risk Assessment; Alcohol Drinking; Adult; Risk Factors; Genetic Predisposition to Disease; United Kingdom; Genetic Risk Score
PubMed: 38727677
DOI: 10.1097/HC9.0000000000000431 -
Journal of Atherosclerosis and... Jul 2024
Topics: Humans; Atherosclerosis; Multifactorial Inheritance; Genetic Predisposition to Disease; Risk Assessment; Risk Factors; Cardiovascular Diseases; Genome-Wide Association Study; Heart Disease Risk Factors; Genetic Risk Score
PubMed: 38369334
DOI: 10.5551/jat.ED254 -
Molecular Biology and Evolution Aug 2023Sighthounds, a distinctive group of hounds comprising numerous breeds, have their origins rooted in ancient artificial selection of dogs. In this study, we performed...
Sighthounds, a distinctive group of hounds comprising numerous breeds, have their origins rooted in ancient artificial selection of dogs. In this study, we performed genome sequencing for 123 sighthounds, including one breed from Africa, six breeds from Europe, two breeds from Russia, and four breeds and 12 village dogs from the Middle East. We gathered public genome data of five sighthounds and 98 other dogs as well as 31 gray wolves to pinpoint the origin and genes influencing the morphology of the sighthound genome. Population genomic analysis suggested that sighthounds originated from native dogs independently and were comprehensively admixed among breeds, supporting the multiple origins hypothesis of sighthounds. An additional 67 published ancient wolf genomes were added for gene flow detection. Results showed dramatic admixture of ancient wolves in African sighthounds, even more than with modern wolves. Whole-genome scan analysis identified 17 positively selected genes (PSGs) in the African population, 27 PSGs in the European population, and 54 PSGs in the Middle Eastern population. None of the PSGs overlapped in the three populations. Pooled PSGs of the three populations were significantly enriched in "regulation of release of sequestered calcium ion into cytosol" (gene ontology: 0051279), which is related to blood circulation and heart contraction. In addition, ESR1, JAK2, ADRB1, PRKCE, and CAMK2D were under positive selection in all three selected groups. This suggests that different PSGs in the same pathway contributed to the similar phenotype of sighthounds. We identified an ESR1 mutation (chr1: g.42,177,149 T > C) in the transcription factor (TF) binding site of Stat5a and a JAK2 mutation (chr1: g.93,277,007 T > A) in the TF binding site of Sox5. Functional experiments confirmed that the ESR1 and JAK2 mutation reduced their expression. Our results provide new insights into the domestication history and genomic basis of sighthounds.
Topics: Dogs; Animals; Wolves; Multifactorial Inheritance; Genome; Genomics; Base Sequence
PubMed: 37433053
DOI: 10.1093/molbev/msad158 -
PLoS Genetics Dec 2023Mendelian randomization (MR) is an effective approach for revealing causal risk factors that underpin complex traits and diseases. While MR has been more widely applied...
Mendelian randomization (MR) is an effective approach for revealing causal risk factors that underpin complex traits and diseases. While MR has been more widely applied under two-sample settings, it is more promising to be used in one single large cohort given the rise of biobank-scale datasets that simultaneously contain genotype data, brain imaging data, and matched complex traits from the same individual. However, most existing multivariable MR methods have been developed for two-sample setting or a small number of exposures. In this study, we introduce a one-sample multivariable MR method based on partial least squares and Lasso regression (MR-PL). MR-PL is capable of considering the correlation among exposures (e.g., brain imaging features) when the number of exposures is extremely upscaled, while also correcting for winner's curse bias. We performed extensive and systematic simulations, and demonstrated the robustness and reliability of our method. Comprehensive simulations confirmed that MR-PL can generate more precise causal estimates with lower false positive rates than alternative approaches. Finally, we applied MR-PL to the datasets from UK Biobank to reveal the causal effects of 36 white matter tracts on 180 complex traits, and showed putative white matter tracts that are implicated in smoking, blood vascular function-related traits, and eating behaviors.
Topics: Humans; Biological Specimen Banks; Mendelian Randomization Analysis; Multifactorial Inheritance; Reproducibility of Results; Neuroimaging; Genome-Wide Association Study; Polymorphism, Single Nucleotide
PubMed: 38150468
DOI: 10.1371/journal.pgen.1011112 -
BMC Genomics Sep 2023Developing genomic resources for a diverse range of species is an important step towards understanding the mechanisms underlying complex traits. Specifically, organisms...
BACKGROUND
Developing genomic resources for a diverse range of species is an important step towards understanding the mechanisms underlying complex traits. Specifically, organisms that exhibit unique and accessible phenotypes-of-interest allow researchers to address questions that may be ill-suited to traditional model organisms. We sequenced the genome and transcriptome of Alston's singing mouse (Scotinomys teguina), an emerging model for social cognition and vocal communication. In addition to producing advertisement songs used for mate attraction and male-male competition, these rodents are diurnal, live at high-altitudes, and are obligate insectivores, providing opportunities to explore diverse physiological, ecological, and evolutionary questions.
RESULTS
Using PromethION, Illumina, and PacBio sequencing, we produced an annotated genome and transcriptome, which were validated using gene expression and functional enrichment analyses. To assess the usefulness of our assemblies, we performed single nuclei sequencing on cells of the orofacial motor cortex, a brain region implicated in song coordination, identifying 12 cell types.
CONCLUSIONS
These resources will provide the opportunity to identify the molecular basis of complex traits in singing mice as well as to contribute data that can be used for large-scale comparative analyses.
Topics: Male; Animals; Mice; Genomics; Biological Evolution; Multifactorial Inheritance; Phenotype; Reproduction
PubMed: 37749493
DOI: 10.1186/s12864-023-09678-7 -
Genes Sep 2023Keratoconus is a corneal dystrophy that is one of the main causes of corneal transplantation and for which there is currently no effective treatment for all patients....
Keratoconus is a corneal dystrophy that is one of the main causes of corneal transplantation and for which there is currently no effective treatment for all patients. The presentation of this disease in pediatric age is associated with rapid progression, a worse prognosis and, in 15-20% of cases, the need for corneal transplantation. It is a multifactorial disease with genetic variability, which makes its genetic study difficult. Discovering new therapeutic targets is necessary to improve the quality of life of patients. In this manuscript, we present the results of whole-exome sequencing (WES) of 24 pediatric families diagnosed at the University Hospital La Paz (HULP) in Madrid. The results show an oligogenic inheritance of the disease. Genes involved in the structure, function, cell adhesion, development and repair pathways of the cornea are proposed as candidate genes for the disease. Further studies are needed to confirm the involvement of the candidate genes described in this article in the development of pediatric keratoconus.
Topics: Humans; Child; Keratoconus; Exome Sequencing; Quality of Life; Cornea; Corneal Dystrophies, Hereditary
PubMed: 37895187
DOI: 10.3390/genes14101838