Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of ...common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency (MC4R)) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification.
Variants in ABCB1 and CYP2C19 have been identified as predictors of cardiac events during clopidogrel therapy initiated after myocardial infarction (MI) or percutaneous coronary intervention (PCI). ...In addition, PON1 has recently been associated with stent thrombosis. The reported effects of these variants have not yet been replicated in a real–world setting. We used BioVU, the Vanderbilt DNA repository linked to de–identified electronic health records (EHRs), to find data on patients who were on clopidogrel treatment after an MI and/or a PCI; among these, we identified those who had experienced one or more recurrent cardiac events while on treatment (cases, n = 225) and those who had not experienced any cardiac event while on treatment (controls, n = 468). We found that CYP2C19*2 (hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.16–2.06, P = 0.003) and ABCB1 (HR 1.28, 95% CI 1.04–1.57, P = 0.018), but not PON1 (HR 0.91, 95% CI 0.73–1.12, P = 0.370), were associated with recurrent events. In this population, genetic signals for clopidogrel resistance in ABCB1 and CYP2C19 were replicated, supporting the use of EHRs for pharmacogenomic studies. Our data do not show an association between PON1 and recurrent cardiovascular events.
Clinical Pharmacology & Therapeutics (2012); 91 2, 257–263. doi:10.1038/clpt.2011.221
Recurrent pathogenic copy number variants (pCNVs) have large-effect impacts on brain function and represent important etiologies of neurodevelopmental psychiatric disorders (NPDs), including autism ...and schizophrenia. Patterns of health care utilization in adults with pCNVs have gone largely unstudied and are likely to differ in significant ways from those of children.
We compared the prevalence of NPDs and electronic health record–based medical conditions in 928 adults with 26 pCNVs to a demographically-matched cohort of pCNV-negative controls from >135,000 patient-participants in Geisinger’s MyCode Community Health Initiative. We also evaluated 3 quantitative health care utilization measures (outpatient, inpatient, and emergency department visits) in both groups.
Adults with pCNVs (24.9%) were more likely than controls (16.0%) to have a documented NPD. They had significantly higher rates of several chronic diseases, including diabetes (29.3% in participants with pCNVs vs 20.4% in participants without pCNVs) and dementia (2.2% in participants with pCNVs vs 1.0% participants without pCNVs), and twice as many annual emergency department visits.
These findings highlight the potential for genetic information—specifically, pCNVs—to inform the study of health care outcomes and utilization in adults. If, as our findings suggest, adults with pCNVs have poorer health and require disproportionate health care resources, early genetic diagnosis paired with patient-centered interventions may help to anticipate problems, improve outcomes, and reduce the associated economic burden.
IMPORTANCE: Population screening for medically relevant genomic variants that cause diseases such as hereditary cancer and cardiovascular disorders is increasing to facilitate early disease detection ...or prevention. Neuropsychiatric disorders (NPDs) are common, complex disorders with clear genetic causes; yet, access to genetic diagnosis is limited. We explored whether inclusion of NPD in population-based genomic screening programs is warranted by assessing 3 key factors: prevalence, penetrance, and personal utility. OBJECTIVE: To evaluate the suitability of including pathogenic copy number variants (CNVs) associated with NPD in population screening by determining their prevalence and penetrance and exploring the personal utility of disclosing results. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, the frequency of 31 NPD CNVs was determined in patient-participants via exome data. Associated clinical phenotypes were assessed using linked electronic health records. Nine CNVs were selected for disclosure by licensed genetic counselors, and participants’ psychosocial reactions were evaluated using a mixed-methods approach. A primarily adult population receiving medical care at Geisinger, a large integrated health care system in the United States with the only population-based genomic screening program approved for medically relevant results disclosure, was included. The cohort was identified from the Geisinger MyCode Community Health Initiative. Exome and linked electronic health record data were available for this cohort, which was recruited from February 2007 to April 2017. Data were collected for the qualitative analysis April 2017 through February 2018. Analysis began February 2018 and ended December 2019. MAIN OUTCOMES AND MEASURES: The planned outcomes of this study include (1) prevalence estimate of NPD-associated CNVs in an unselected health care system population; (2) penetrance estimate of NPD diagnoses in CNV-positive individuals; and (3) qualitative themes that describe participants’ responses to receiving NPD-associated genomic results. RESULTS: Of 90 595 participants with CNV data, a pathogenic CNV was identified in 708 (0.8%; 436 women 61.6%; mean SD age, 50.04 18.74 years). Seventy percent (n = 494) had at least 1 associated clinical symptom. Of these, 28.8% (204) of CNV-positive individuals had an NPD code in their electronic health record, compared with 13.3% (11 835 of 89 887) of CNV-negative individuals (odds ratio, 2.21; 95% CI, 1.86-2.61; P < .001); 66.4% (470) of CNV-positive individuals had a history of depression and anxiety compared with 54.6% (49 118 of 89 887) of CNV-negative individuals (odds ratio, 1.53; 95% CI, 1.31-1.80; P < .001). 16p13.11 (71 0.078%) and 22q11.2 (108 0.119%) were the most prevalent deletions and duplications, respectively. Only 5.8% of individuals (41 of 708) had a previously known genetic diagnosis. Results disclosure was completed for 141 individuals. Positive participant responses included poignant reactions to learning a medical reason for lifelong cognitive and psychiatric disabilities. CONCLUSIONS AND RELEVANCE: This study informs critical factors central to the development of population-based genomic screening programs and supports the inclusion of NPD in future designs to promote equitable access to clinically useful genomic information.
Context.
The method of gyrochronology relates the age of its star to its rotation period. However, recent evidence of deviations from gyrochronology relations has been reported in the literature.
...Aims.
We study the influence of tidal interaction between a star and its companion on the rotation velocity of the star to explain peculiar stellar rotation velocities.
Methods.
We followed the interaction of a star and its planet using a comprehensive numerical framework that combines tidal friction, magnetic braking, planet migration, and detailed stellar evolution models from the GARSTEC grid. We focus on close-in companions from 1 to 20
M
Jup
orbiting low-mass (0.8 − 1
M
⊙
) main-sequence stars with a broad metallicity of Fe/H = − 1 up to solar.
Results.
Our simulations suggest that the dynamical interaction between a star and its companion can have different outcomes that depend on the initial semi-major axis and the mass of the planet, as well as on the mass and metallicity of its host star. In most cases, especially in the case of planet engulfment, we find a catastrophic increase in stellar rotation velocity from 1 kms
−1
to over 40 kms
−1
while the star is still on the main-sequence. The main prediction of our model is that low-mass main-sequence stars with abnormal rotation velocities should be more common at low-metallicity, as lower Fe/H favours faster planet engulfment, based on the assumption that the occurrence rate of close-in massive planets is similar at all metallicities.
Conclusions.
Our scenario explains peculiar rotation velocities of low-mass main-sequence stars by the tidal interaction between the star and its companion. Current observational samples are too narrow and incomplete, and, thus, they are not sufficient for our model to be tested.
Europe has played a major role in dog evolution, harbouring the oldest uncontested Palaeolithic remains and having been the centre of modern dog breed creation. Here we sequence the genomes of an ...Early and End Neolithic dog from Germany, including a sample associated with an early European farming community. Both dogs demonstrate continuity with each other and predominantly share ancestry with modern European dogs, contradicting a previously suggested Late Neolithic population replacement. We find no genetic evidence to support the recent hypothesis proposing dual origins of dog domestication. By calibrating the mutation rate using our oldest dog, we narrow the timing of dog domestication to 20,000-40,000 years ago. Interestingly, we do not observe the extreme copy number expansion of the AMY2B gene characteristic of modern dogs that has previously been proposed as an adaptation to a starch-rich diet driven by the widespread adoption of agriculture in the Neolithic.
IMPORTANCE: Cerebral palsy is a common neurodevelopmental disorder affecting movement and posture that often co-occurs with other neurodevelopmental disorders. Individual cases of cerebral palsy are ...often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases. OBJECTIVE: To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of patients with cerebral palsy that included a clinical laboratory referral cohort with data accrued between 2012 and 2018 and a health care–based cohort with data accrued between 2007 and 2017. EXPOSURES: Exome sequencing with copy number variant detection. MAIN OUTCOMES AND MEASURES: The primary outcome was the molecular diagnostic yield of exome sequencing. RESULTS: Among 1345 patients from the clinical laboratory referral cohort, the median age was 8.8 years (interquartile range, 4.4-14.7 years; range, 0.1-66 years) and 601 (45%) were female. Among 181 patients in the health care–based cohort, the median age was 41.9 years (interquartile range, 28.0-59.6 years; range, 4.8-89 years) and 96 (53%) were female. The molecular diagnostic yield of exome sequencing was 32.7% (95% CI, 30.2%-35.2%) in the clinical laboratory referral cohort and 10.5% (95% CI, 6.0%-15.0%) in the health care–based cohort. The molecular diagnostic yield ranged from 11.2% (95% CI, 6.4%-16.2%) for patients without intellectual disability, epilepsy, or autism spectrum disorder to 32.9% (95% CI, 25.7%-40.1%) for patients with all 3 comorbidities. Pathogenic and likely pathogenic variants were identified in 229 genes (29.5% of 1526 patients); 86 genes were mutated in 2 or more patients (20.1% of 1526 patients) and 10 genes with mutations were independently identified in both cohorts (2.9% of 1526 patients). CONCLUSIONS AND RELEVANCE: Among 2 cohorts of patients with cerebral palsy who underwent exome sequencing, the prevalence of pathogenic and likely pathogenic variants was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Further research is needed to understand the clinical implications of these findings.
Most genetic analyses of ancient and modern dogs have focused on variation in the autosomes or on the mitochondria. Mitochondrial DNA is more easily obtained from ancient samples than nuclear DNA and ...mitochondrial analyses have revealed important insights into the evolutionary history of canids. Utilizing a recently published dog Y-chromosome reference, we analyzed Y-chromosome sequence across a diverse collection of canids and determined the Y haplogroup of three ancient European dogs.
We identified 1121 biallelic Y-chromosome SNVs using whole-genome sequences from 118 canids and defined variants diagnostic to distinct dog Y haplogroups. Similar to that of the mitochondria and previous more limited studies of Y diversity, we observe several deep splits in the Y-chromosome tree which may be the result of retained Y-chromosome diversity which predates dog domestication or post-domestication admixture with wolves. We find that Y-chromosomes from three ancient European dogs (4700-7000 years old) belong to distinct clades.
We estimate that the time to the most recent comment ancestor of dog Y haplogroups is 68-151 thousand years ago. Analysis of three Y-chromosomes from the Neolithic confirms long stranding population structure among European dogs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: An increased risk of venous thromboembolism (VTE) has been reported in men with an additional sex chromosome. The association between other sex chromosome aneuploidies and VTE is not well ...characterized. OBJECTIVE: To determine if sex chromosome aneuploidy is associated with VTE. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of sex chromosome aneuploidy and VTE, performed by analyzing X- and Y-chromosome dosage and VTE incidence in 642 544 individuals from 2 population-scale biobanks: the US Geisinger MyCode Community Health Initiative (N = 154 519) and the UK Biobank (N = 488 025); analysis was limited to participants self-identified as White because of inadequate sample sizes for other race and ethnicity groups. A total of 108 461 unrelated MyCode participants with electronic health record follow-up ranging from September 1996 to December 2020 and 418 725 unrelated British and Irish UK Biobank participants who attended the baseline assessment between March 2006 and October 2010, with follow-up extending to November 2020, were included in analyses of VTE. EXPOSURES: Sex chromosome aneuploidies. MAIN OUTCOMES AND MEASURES: Individuals with 1 primary inpatient VTE diagnosis, 2 primary outpatient VTE diagnoses, or a self-reported VTE diagnosis were defined as VTE cases. P values were adjusted for multiple comparisons. RESULTS: Identification of sex chromosome aneuploidy was undertaken among 642 544 individuals aged 18 to 90 years. Identification of a diagnosis of VTE was undertaken among 108 461 unrelated MyCode participants (65 565 60.5% female; mean age at last visit, 58.0 SD, 17.6 years; median follow-up, 15.3 IQR, 9.7 years) and among 418 725 unrelated UK Biobank participants (224 695 53.7% female; mean age at baseline interview, 56.9 SD, 8.0 years; median follow-up, 12.0 IQR, 1.6 years). Among MyCode participants, during 10 years of follow-up, 17 incident VTE events per 1353 person-years were detected among those with supernumerary sex chromosome aneuploidy (1.3% per person-year) compared with 2060 per 816 682 person-years among those with 46,XX or 46,XY (0.25% per person-year) (hazard ratio, 5.4 95% CI, 3.4-8.7; 10-year risk difference, 8.8% 95% CI, 4.2%-14.0%; P < .001). Among UK Biobank participants, during 10 years of follow-up, 16 incident VTE events per 3803 person-years were detected among those with supernumerary sex chromosome aneuploidy (0.42% per person-year) compared with 4491 per 3 970 467 person-years among those with 46,XX or 46,XY (0.11% per person-year) (hazard ratio, 4.1 95% CI, 2.5-6.7; 10-year risk difference, 3.7% 95% CI, 1.4%-5.9%; P < .001). CONCLUSIONS AND RELEVANCE: Adults with supernumerary sex chromosome aneuploidies compared with 2 sex chromosomes had a small but statistically significant increased risk of VTE. Further research is needed to understand the clinical implications of this association.
PDF
