Search

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., Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals. Here, Oetjens et al. systematically study the contribution of common genetic variation to variable expressivity of RGDs and find it is frequently influenced by polygenic factors identified in genome-wide association studies of relevant traits.

Genomic variants that cause neurodevelopmental/psychiatric disorders (NPD) are relatively prevalent and highly penetrant. This study aimed to understand adults’ immediate responses to receiving NPD-related results to inform inclusion in population-based genomic screening programs. Nine recurrent, pathogenic copy number variants (CNVs) were identified from research exome data, clinically confirmed, and disclosed to adult participants of the Geisinger MyCode Community Health Initiative DiscovEHR cohort by experienced genetic counselors. A subset of in-person genetic counseling sessions (n = 27) were audio-recorded, transcribed, and coded using a grounded theory approach. Participant reactions were overwhelmingly positive and indicated that an NPD genetic etiology was highly valuable and personally useful. Participants frequently reported learning disabilities or other NPD that were not documented in their electronic health records and noted difficulties obtaining support for NPD needs. Most intended to share their genetic result with family members and health care providers and were interested in how their result could improve their healthcare. This study indicates that results from population-based NPD genomic screening can provide personal value for adults with NPD, were viewed positively by participants, and could improve clinical outcomes by informing symptom monitoring for NPD and co-morbidities, promoting improved health behaviors, and enhancing psychotherapeutic approaches.

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.

Exome and genome sequencing are increasingly utilized in research studies and clinical care and can provide clinically relevant information beyond the initial intent for sequencing, including medically actionable secondary findings. Despite ongoing debate about sharing this information with patients and participants, a growing number of clinical laboratories and research programs routinely report secondary findings that increase the risk for selected diseases. Recently, there has been a push to maximize the potential benefit of this practice by implementing proactive genomic screening at the population level irrespective of medical history, but the feasibility of deploying population-scale proactive genomic screening requires scaling key elements of the genomic data evaluation process. Herein, we describe the motivation, development, and implementation of a population-scale variant-first screening pipeline combining bioinformatics-based filtering with a manual review process to screen for clinically relevant findings in research exomes generated through the DiscovEHR collaboration within Geisinger's MyCode® research project. Consistent with other studies, this pipeline yields a screen-positive detection rate between 2.1 and 2.6% (depending on inclusion of those with prior indication-based testing) in 130,048 adult MyCode patient-participants screened for clinically relevant findings in 60 genes. Our variant-first pipeline affords cost and time savings by filtering out negative cases, thereby avoiding analysis of each exome one-by-one, as typically employed in the diagnostic setting. While research is still needed to fully appreciate the benefits of population genomic screening, MyCode provides the first demonstration of a program at scale to help shape how population genomic screening is integrated into routine clinical care.

The male specific regions of primate Y-chromosomes (MSY) are enriched for multi-copy genes highly expressed in the testis. These genes are located in large repetitive sequences arranged as palindromes, inverted-, and tandem-repeats termed amplicons. In humans, these genes have critical roles in male fertility and are essential for the production of sperm. The structure of human and chimpanzee amplicon sequences show remarkable difference relative to the remainder of the genome, a difference that may be the result of intense selective pressure on male fertility. Four populations of common chimpanzees have undergone extended periods of isolation and appear to be in the early process of speciation. A recent study found amplicons enriched for testis-expressed genes on the primate X-chromosome the target of hard selective sweeps, and male-fertility genes on the Y-chromosome may also be the targets of selection. However, little is understood about Y-chromosome amplicon diversity within and across chimpanzee populations. Here, we analyze 9 common chimpanzee (representing three subspecies: Pan troglodytes schweinfurthii, Pan troglodytes ellioti, and Pan troglodytes verus) and two bonobo (Pan paniscus) male whole-genome sequences to assess Y ampliconic copy-number diversity across the Pan genus. We observe that the copy-number of Y chromosome amplicons is variable amongst chimpanzees and bonobos, and identify several lineage-specific patterns, including variable copy-number of azoospermia candidates RBMY and DAZ. We detect recurrent switchpoints of copy-number change along the ampliconic tracts across chimpanzee populations, which may be the result of localized genome instability or selective forces.

Advances in genotyping technology have, over the past decade, enabled the focused search for common genetic variation associated with human diseases and traits. With the recently increased availability of detailed phenotypic data from electronic health records and epidemiological studies, the impact of one or more genetic variants on the phenome is starting to be characterized both in clinical and population-based settings using phenome-wide association studies (PheWAS). These studies reveal a number of challenges that will need to be overcome to unlock the full potential of PheWAS for the characterization of the complex human genome-phenome relationship.

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 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.

Background Empirical data on conditions that increase risk of coronavirus disease 2019 (COVID-19) progression are needed to identify high risk individuals. We performed a comprehensive quantitative assessment of pre-existing clinical phenotypes associated with COVID-19-related hospitalization. Methods Phenome-wide association study (PheWAS) of SARS-CoV-2-positive patients from an integrated health system (Geisinger) with system-level outpatient/inpatient COVID-19 testing capacity and retrospective electronic health record (EHR) data to assess pre-COVID-19 pandemic clinical phenotypes associated with hospital admission (hospitalization). Results Of 12,971 individuals tested for SARS-CoV-2 with sufficient pre-COVID-19 pandemic EHR data at Geisinger, 1604 were SARS-CoV-2 positive and 354 required hospitalization. We identified 21 clinical phenotypes in 5 disease categories meeting phenome-wide significance (P-4), including: six kidney phenotypes, e.g. end stage renal disease or stage 5 CKD (OR = 11.07, p = 1.96x10-8), six cardiovascular phenotypes, e.g. congestive heart failure (OR = 3.8, p = 3.24x10-5), five respiratory phenotypes, e.g. chronic airway obstruction (OR = 2.54, p = 3.71x10-5), and three metabolic phenotypes, e.g. type 2 diabetes (OR = 1.80, p = 7.51x10-5). Additional analyses defining CKD based on estimated glomerular filtration rate, confirmed high risk of hospitalization associated with pre-existing stage 4 CKD (OR 2.90, 95% CI: 1.47, 5.74), stage 5 CKD/dialysis (OR 8.83, 95% CI: 2.76, 28.27), and kidney transplant (OR 14.98, 95% CI: 2.77, 80.8) but not stage 3 CKD (OR 1.03, 95% CI: 0.71, 1.48). Conclusions This study provides quantitative estimates of the contribution of pre-existing clinical phenotypes to COVID-19 hospitalization and highlights kidney disorders as the strongest factors associated with hospitalization in an integrated US healthcare system.

Background 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (10.1186/s12864-018-4749-z) contains supplementary material, which is available to authorized users.

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., The European continent is thought to have played a major role in the origins of modern dogs. Here, analysing two ancient dog genomes from Germany, the authors find significant genetic continuity throughout the Neolithic period and time dog domestication to ∼20,000–40,000 years ago.

Aim: We sought to identify potential pleiotropy involving pharmacogenes. Methods: We tested 184 functional variants in 34 pharmacogenes for associations using a custom grouping of International Classification and Disease, Ninth Revision billing codes extracted from deidentified electronic health records of 6892 patients. Results: We replicated several associations including ABCG2 (rs2231142) and gout (p = 1.73 × 10-7; odds ratio [OR]: 1.73; 95% CI: 1.40–2.12); and SLCO1B1 (rs4149056) and jaundice (p = 2.50 × 10-4; OR: 1.67; 95% CI: 1.27–2.20). Conclusion: In this systematic screen for phenotypic associations with functional variants, several novel genotype–phenotype combinations also achieved phenome-wide significance, including SLC15A2 rs1143672 and renal osteodystrophy (p = 2.67 × 10- 6; OR: 0.61; 95% CI: 0.49–0.75).

Population stratification or confounding by genetic ancestry is a potential cause of false associations in genetic association studies. Estimation of and adjustment for genetic ancestry has become common practice thanks in part to the availability of ancestry informative markers on genome-wide association study (GWAS) arrays. While array data is now widespread, these data are not ubiquitous as several large epidemiologic and clinic-based studies lack genome-wide data. One such large epidemiologic-based study lacking genome-wide data accessible to investigators is the National Health and Nutrition Examination Surveys (NHANES), population-based cross-sectional surveys of Americans linked to demographic, health, and lifestyle data conducted by the Centers for Disease Control and Prevention. DNA samples (n=14,998) were extracted from biospecimens from consented NHANES participants between 1991-1994 (NHANES III, phase 2) and 1999-2002 and represent three major self-identified racial/ethnic groups: non-Hispanic whites (n=6,634), non-Hispanic blacks (n=3,458), and Mexican Americans (n=3,950). We as the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study genotyped candidate gene and GWAS-identified index variants in NHANES as part of the larger Population Architecture using Genomics and Epidemiology (PAGE) I study for collaborative genetic association studies. To enable basic quality control such as estimation of genetic ancestry to control for population stratification in NHANES san genome-wide data, we outline here strategies that use limited genetic data to identify the markers optimal for characterizing genetic ancestry. From among 411 and 295 autosomal SNPs available in NHANES III and NHANES 1999-2002, we demonstrate that markers with ancestry information can be identified to estimate global ancestry. Despite limited resolution, global genetic ancestry is highly correlated with self-identified race for the majority of participants, although less so for ethnicity. Overall, the strategies outlined here for a large epidemiologic study can be applied to other datasets accessible for genotype phenotype studies but are sans genome-wide data.

Plasma concentration of plasminogen activator inhibitor-1 (PAI-1) is highly correlated with several cardiovascular disease (CVD) risk factors. It also plays a direct role in CVD, including myocardial infarction and stroke, by impeding the dissolution of thrombi in the blood. Insofar as PAI-1 links CVD's risk factors to its endpoints, genetic variants modulating the relationship between PAI-1 and risk factors may be of particular clinical and biological interest. The high heritability of PAI-1, which has not been explained by genetic association studies, may also, in large part, be due to this relationship with CVD risk factors. Using exome-wide data from 1,032 Ghanaian study participants, we tested for heterogeneity of correlation by genotype between PAI-1 and 4 CVD risk factors (body mass index, triglycerides, mean arterial pressure, and fasting glucose) under the hypothesis that loci involved in the relationship between PAI-1 and other risk factors will also modify their correlational structure. We found more significant heterogeneities of correlation by genotype than we found marginal effects, with no evidence of type I inflation. The most significant result among all univariate and multivariate tests performed in this study was the heterogeneity of correlation between PAI-1 and mean arterial pressure at rs10738554, near SLC24A2, a gene previously associated with high blood pressure in African Americans.

Summary BackgroundVKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. MethodsWe did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 −1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p

Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition., Children's Discovery Institute, March of Dimes Birth Defects Foundation, National Institute of General Medical Sciences (U.S.) (T32 GM081739), Washington University (Saint Louis, Mo.), Washington University (Saint Louis, Mo.) (Mr. and Mrs. Spencer T. Olin Fellowship for Women in Graduate Study), Sigrid Jusélius stiftelse, Signe and Anne Gyllenberg Foundation, Academy of Finland