Publications by authors named "Neil Risch"

143 Publications

The difficulties of broad data sharing in genomic medicine: Empirical evidence from diverse participants in prenatal and pediatric clinical genomics research.

Genet Med 2022 Feb 30;24(2):410-418. Epub 2021 Nov 30.

Program in Bioethics, University of California San Francisco, San Francisco, CA; Department of Social & Behavioral Sciences, School of Nursing, University of California San Francisco, San Francisco, CA.

Purpose: This study aimed to understand broad data sharing decisions among predominantly underserved families participating in genomic research.

Methods: Drawing on clinic observations, semistructured interviews, and survey data from prenatal and pediatric families enrolled in a genomic medicine study focused on historically underserved and underrepresented populations, this paper expands empirical evidence regarding genomic data sharing communication and decision-making.

Results: One-third of parents declined to share family data, and pediatric participants were significantly more likely to decline than prenatal participants. The pediatric population was significantly more socioeconomically disadvantaged and more likely to require interpreters. Opt-in was tied to altruism and participants' perception that data sharing was inherent to research participation. Opt-out was associated with privacy concerns and influenced by clinical staff's presentation of data handling procedures. The ability of participants to make informed choices during enrollment about data sharing was weakened by suboptimal circumstances, which was revealed by poor understanding of data sharing in follow-up interviews as well as discrepancies between expressed participant desires and official recorded choices.

Conclusion: These empirical data suggest that the context within which informed consent process is conducted in clinical genomics may be inadequate for respecting participants' values and preferences and does not support informed decision-making processes.
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http://dx.doi.org/10.1016/j.gim.2021.09.021DOI Listing
February 2022

QT Interval Dynamics and Cardiovascular Outcomes: A Cohort Study in an Integrated Health Care Delivery System.

J Am Heart Assoc 2021 10 28;10(19):e018513. Epub 2021 Sep 28.

Division of Research Kaiser Permanente Oakland CA.

Background Long QT has been associated with ventricular dysrhythmias, cardiovascular disease (CVD) mortality, and sudden cardiac death. However, no studies to date have investigated the dynamics of within-person QT change over time in relation to risk of incident CVD and all-cause mortality in a real-world setting. Methods and Results A cohort study among members of an integrated health care delivery system in Northern California including 61 455 people (mean age, 62 years; 60% women, 42% non-White) with 3 or more ECGs (baseline in 2005-2009; mean±SD follow-up time, 7.6±2.6 years). In fully adjusted models, tertile 3 versus tertile 1 of average QT corrected (using the Fridericia correction) was associated with cardiac arrest (hazard ratio [HR], 1.66), heart failure (HR, 1.62), ventricular dysrhythmias (HR, 1.56), all CVD (HR, 1.31), ischemic heart disease (HR, 1.28), total stroke (HR, 1.18), and all-cause mortality (HR, 1.24). Tertile 3 versus tertile 2 of the QT corrected linear slope was associated with cardiac arrest (HR, 1.22), ventricular dysrhythmias (HR, 1.12), and all-cause mortality (HR, 1.09). Tertile 3 versus tertile 1 of the QT corrected root mean squared error was associated with ventricular dysrhythmias (HR, 1.34), heart failure (HR, 1.28), all-cause mortality (HR, 1.20), all CVD (HR, 1.14), total stroke (HR, 1.08), and ischemic heart disease (HR, 1.07). Conclusions Our results demonstrate improved predictive ability for CVD outcomes using longitudinal information from serial ECGs. Long-term average QT corrected was more strongly associated with CVD outcomes than the linear slope or the root mean squared error. This new evidence is clinically relevant because ECGs are frequently used, noninvasive, and inexpensive.
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http://dx.doi.org/10.1161/JAHA.120.018513DOI Listing
October 2021

Torsade de pointes: A nested case-control study in an integrated healthcare delivery system.

Ann Noninvasive Electrocardiol 2022 01 21;27(1):e12888. Epub 2021 Sep 21.

Division of Research, Kaiser Permanente, Oakland, CA, USA.

Background: TdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia.

Objective: Our goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real-world healthcare setting.

Methods: Case-control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow-up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018.

Results: A total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non-white. The independent predictors of TdP were potassium concentration <3.6 mEq/L (OR = 10.6), prior history of atrial fibrillation/flutter (OR = 6.2), QTc >480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in-hospital and 1-year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively.

Conclusions: These findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy.
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http://dx.doi.org/10.1111/anec.12888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8739596PMC
January 2022

A unified framework identifies new links between plasma lipids and diseases from electronic medical records across large-scale cohorts.

Nat Genet 2021 07 17;53(7):972-981. Epub 2021 Jun 17.

Department of Genetics and Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify new lipid-associated genes and study the relationships among lipids, genotypes, gene expression and hundreds of complex human diseases from the Electronic Medical Records and Genomics (347 traits) and the UK Biobank (549 traits). Aside from 67 new lipid-associated genes with strong replication, we found evidence for pleiotropic SNPs/genes between lipids and diseases across the phenome. These include discordant pleiotropy in the HLA region between lipids and multiple sclerosis and putative causal paths between triglycerides and gout, among several others. Our findings give insights into the genetic basis of the relationship between plasma lipids and diseases on a phenome-wide scale and can provide context for future prevention and treatment strategies.
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http://dx.doi.org/10.1038/s41588-021-00879-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555954PMC
July 2021

Effect of SLCO1B1 T521C on Statin-Related Myotoxicity With Use of Lovastatin and Atorvastatin.

Clin Pharmacol Ther 2021 09 23;110(3):733-740. Epub 2021 Jul 23.

Department of Clinical Pharmacy, University of California San Francisco, San Francisco, California, USA.

The association between the c.521T>C variant allele in SLCO1B1 (reference single nucleotide polymorphism (rs)4149056) and simvastatin-induced myotoxicity was discovered over a decade ago; however, whether this relationship represents a class effect is still not fully known. The aim of this study was to investigate the relationship between rs4149056 genotype and statin-induced myotoxicity in patients taking atorvastatin and lovastatin. Study participants were from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. A total of 233 statin-induced myopathy + rhabdomyolysis cases met the criteria for inclusion and were matched to 2,342 controls. To validate the drug response phenotype, we replicated the previously established association between rs4149056 genotype and simvastatin-induced myotoxicity. In particular, compared with homozygous T allele carriers, there was a significantly increased risk of simvastatin-induced myopathy + rhabdomyolysis in homozygous carriers of the C allele (CC vs. TT, odds ratio [OR] 4.62, 95% confidence interval [CI] 1.58-11.90, P = 0.003). For lovastatin users, homozygous carriers of the C allele were also at increased risk of statin-induced myopathy + rhabdomyolysis (CC vs. TT, OR 4.49, 95% CI 1.68-10.80, P = 0.001). In atorvastatin users, homozygous carriers of the C allele were twice as likely to experience statin-induced myopathy, though this association did not achieve statistical significance (CC vs. TT, OR 2.00, 95% CI 0.44-6.59, P = 0.30). In summary, our findings suggest that the association of rs4149056 with simvastatin-related myotoxicity may also extend to lovastatin. More data is needed to determine the extent of the association in atorvastatin users. Altogether, these data expand the evidence base for informing guidelines of pharmacogenetic-based statin prescribing practices.
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http://dx.doi.org/10.1002/cpt.2337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376784PMC
September 2021

Challenges in providing residual risks in carrier testing.

Prenat Diagn 2021 Aug 13;41(9):1049-1056. Epub 2021 Jun 13.

Institute for Human Genetics and Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA.

The probability an individual is a carrier for a recessive disorder despite a negative carrier test, referred to as residual risk, has been part of carrier screening for over 2 decades. Residual risks are calculated by subtracting the frequency of carriers of pathogenic variants detected by the test from the carrier frequency in a population, estimated from the incidence of the disease. Estimates of the incidence (and therefore carrier frequency) of many recessive disorders differ among different population groups and are inaccurate or unavailable for many genes on large carrier screening panels for most of the world's populations. The pathogenic variants detected by the test and their frequencies also vary across groups and over time as variants are newly discovered or reclassified, which requires today's residual carrier risks to be continually updated. Even when a residual carrier risk is derived using accurate data obtained in a particular group, it may not apply to many individuals in that group because of misattributed ancestry or unsuspected admixture. Missing or inaccurate data, the challenge of determining meaningful ancestry-specific risks and applying them appropriately, and a lack of evidence they impact management, suggest that patients be counseled that although carrier screening may miss a small fraction of carriers, residual risks with contemporary carrier screening are well below the risk posed by invasive prenatal diagnosis, even if one member of the couple is a carrier, and that efforts to provide precise residual carrier risks are unnecessary.
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http://dx.doi.org/10.1002/pd.5975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453722PMC
August 2021

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Mol Psychiatry 2021 Sep 22;26(9):5239-5250. Epub 2021 Jan 22.

HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
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http://dx.doi.org/10.1038/s41380-020-01006-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295400PMC
September 2021

Genetic ancestry, skin pigmentation, and the risk of cutaneous squamous cell carcinoma in Hispanic/Latino and non-Hispanic white populations.

Commun Biol 2020 12 14;3(1):765. Epub 2020 Dec 14.

Department of Dermatology, Massachusetts General Hospital, Boston, MA, 02114, USA.

Although cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in individuals of European ancestry, the incidence of cSCC in Hispanic/Latinos is also increasing. cSCC has both a genetic and environmental etiology. Here, we examine the role of genetic ancestry, skin pigmentation, and sun exposure in Hispanic/Latinos and non-Hispanic whites on cSCC risk. We observe an increased cSCC risk with greater European ancestry (P = 1.27 × 10) within Hispanic/Latinos and with greater northern (P = 2.38 × 10) and western (P = 2.28 × 10) European ancestry within non-Hispanic whites. These associations are significantly, but not completely, attenuated after considering skin pigmentation-associated loci, history of actinic keratosis, and sun-protected versus sun-exposed anatomical sites. We also report an association of the well-known pigment variant Ala111Thr (rs1426654) at SLC24A5 with cSCC in Hispanic/Latinos. These findings demonstrate a strong correlation of northwestern European genetic ancestry with cSCC risk in both Hispanic/Latinos and non-Hispanic whites, largely but not entirely mediated through its impact on skin pigmentation.
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http://dx.doi.org/10.1038/s42003-020-01461-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736583PMC
December 2020

A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility.

Cancer Res 2021 04 8;81(7):1695-1703. Epub 2020 Dec 8.

Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, California.

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (), as well as a novel candidate gene (), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62, = 2.55 × 10). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137514PMC
April 2021

Identification of 31 loci for mammographic density phenotypes and their associations with breast cancer risk.

Nat Commun 2020 10 9;11(1):5116. Epub 2020 Oct 9.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P < 5 × 10, tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis (P < 0.05). Mendelian randomization analyses show that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are all significantly associated with breast cancer risk (P < 0.05). Pathway analyses reveal distinct biological processes involving DA, NDA and PD loci. These findings provide additional insights into the genetic basis of MD phenotypes and their associations with breast cancer risk.
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http://dx.doi.org/10.1038/s41467-020-18883-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547012PMC
October 2020

The role of exome sequencing in newborn screening for inborn errors of metabolism.

Nat Med 2020 09 10;26(9):1392-1397. Epub 2020 Aug 10.

Department of Plant and Microbial Biology, University of California Berkeley, Berkeley, CA, USA.

Public health newborn screening (NBS) programs provide population-scale ascertainment of rare, treatable conditions that require urgent intervention. Tandem mass spectrometry (MS/MS) is currently used to screen newborns for a panel of rare inborn errors of metabolism (IEMs). The NBSeq project evaluated whole-exome sequencing (WES) as an innovative methodology for NBS. We obtained archived residual dried blood spots and data for nearly all IEM cases from the 4.5 million infants born in California between mid-2005 and 2013 and from some infants who screened positive by MS/MS, but were unaffected upon follow-up testing. WES had an overall sensitivity of 88% and specificity of 98.4%, compared to 99.0% and 99.8%, respectively for MS/MS, although effectiveness varied among individual IEMs. Thus, WES alone was insufficiently sensitive or specific to be a primary screen for most NBS IEMs. However, as a secondary test for infants with abnormal MS/MS screens, WES could reduce false-positive results, facilitate timely case resolution and in some instances even suggest more appropriate or specific diagnosis than that initially obtained. This study represents the largest, to date, sequencing effort of an entire population of IEM-affected cases, allowing unbiased assessment of current capabilities of WES as a tool for population screening.
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http://dx.doi.org/10.1038/s41591-020-0966-5DOI Listing
September 2020

Meta-Analysis of 26 638 Individuals Identifies Two Genetic Loci Associated With Left Ventricular Ejection Fraction.

Circ Genom Precis Med 2020 08 30;13(4):e002804. Epub 2020 Jun 30.

Division of Research, Kaiser Permanente Northern California (KPNC), Oakland, CA (H.C., K.K.T., C.J., D.K.R., A.S.G., N.R., C.S.).

Background: Left ventricular ejection fraction (EF) is an indicator of cardiac function, usually assessed in individuals with heart failure and other cardiac conditions. Although family studies indicate that EF has an important genetic component with heritability estimates up to 0.61, to date only 6 EF-associated loci have been reported.

Methods: Here, we conducted a genome-wide association study (GWAS) of EF in 26 638 adults from the Genetic Epidemiology Research on Adult Health and Aging and the UK Biobank cohorts.

Results: A meta-analysis combining results from Genetic Epidemiology Research on Adult Health and Aging and UK Biobank identified a novel locus: on chromosome 3p25 (rs11719526; β=0.47 and =3.10×10) that replicated in Biobank Japan and confirmed recent findings implicating the locus on chromosome 10q26 in EF variation, with the strongest association observed for rs17617337 (β=-0.83 and =8.24×10). Although the minor allele frequencies of rs11719526 were generally common (between 0.13 and 0.44) in different ethnic groups, rs17617337 was rare (minor allele frequencies<0.05) in Asian and African ancestry populations. These associations were slightly attenuated, after considering antecedent cardiac conditions (ie, heart failure/cardiomyopathy, hypertension, myocardial infarction, atrial fibrillation, valvular disease, and revascularization procedures). This suggests that the effects of the lead variants at or on EF are largely independent of these conditions.

Conclusions: In this large and multiethnic study, we identified 2 loci, and , associated with EF at a genome-wide significance level. Identifying and understanding the genetic determinants of EF is important to better understand the pathophysiology of this strong correlate of cardiac outcomes and to help target the development of future therapies.
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http://dx.doi.org/10.1161/CIRCGEN.119.002804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446727PMC
August 2020

A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness.

Commun Biol 2020 06 11;3(1):301. Epub 2020 Jun 11.

Kaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA, 94612, USA.

Central corneal thickness (CCT) is one of the most heritable human traits, with broad-sense heritability estimates ranging between 0.68 to 0.95. Despite the high heritability and numerous previous association studies, only 8.5% of CCT variance is currently explained. Here, we report the results of a multiethnic meta-analysis of available genome-wide association studies in which we find association between CCT and 98 genomic loci, of which 41 are novel. Among these loci, 20 were significantly associated with keratoconus, and one (RAPSN rs3740685) was significantly associated with glaucoma after Bonferroni correction. Two-sample Mendelian randomization analysis suggests that thinner CCT does not causally increase the risk of primary open-angle glaucoma. This large CCT study explains up to 14.2% of CCT variance and increases substantially our understanding of the etiology of CCT variation. This may open new avenues of investigation into human ocular traits and their relationship to the risk of vision disorders.
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http://dx.doi.org/10.1038/s42003-020-1037-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289804PMC
June 2020

Analysis of putative cis-regulatory elements regulating blood pressure variation.

Hum Mol Genet 2020 07;29(11):1922-1932

Department of Genetic Medicine, McKusick-Nathans Institute, Baltimore, MD 21205, USA.

Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of 'expressed' genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.
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http://dx.doi.org/10.1093/hmg/ddaa098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372556PMC
July 2020

The impact of adjusting for baseline in pharmacogenomic genome-wide association studies of quantitative change.

NPJ Genom Med 2020 16;5. Epub 2020 Jan 16.

2Institute for Human Genetics, University of California, San Francisco, CA 94143 USA.

In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (, and /). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (, , and ). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (/) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change.
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http://dx.doi.org/10.1038/s41525-019-0109-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965183PMC
January 2020

A brief history of human disease genetics.

Nature 2020 01 8;577(7789):179-189. Epub 2020 Jan 8.

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition.
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http://dx.doi.org/10.1038/s41586-019-1879-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405896PMC
January 2020

A novel truncating variant in ring finger protein 113A (RNF113A) confirms the association of this gene with X-linked trichothiodystrophy.

Am J Med Genet A 2020 03 27;182(3):513-520. Epub 2019 Dec 27.

Division of Medical Genetics, University of California, San Francisco, San Francisco, California.

We describe an 11-year old boy with severe global developmental delays, failure to thrive and growth retardation, refractory seizures with recurrent status epilepticus, hypogammaglobulinemia, hypergonadotropic hypogonadism, and duodenal strictures. He had facial and skin findings compatible with trichothiodystrophy, including sparse and brittle hair, thin eyebrows, and dry skin. Exome sequencing showed a hemizygous, truncating variant in RNF113A, c.903_910delGCAGACCA, predicting p.(Gln302fs*12), that was inherited from his mother. Although his clinical features overlap closely with features described in the two previously reported male first cousins with RNF113A loss of function mutations, the duodenal strictures seen in this patient have not been reported. Interestingly, the patient's mother had short stature and 100% skewed X-inactivation as seen in other obligate female carriers. A second male with developmental delays, microcephaly, seizures, ambiguous genitalia, and facial anomalies that included sparse and brittle hair, thin eyebrows and dry skin was recently reported to have c.897_898delTG, predicting p.(Cys299*) in RNF113A and we provide additional clinical details for this patient. This report further supports deleterious variants in RNF113A as a cause of a novel trichothiodystrophy syndrome.
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http://dx.doi.org/10.1002/ajmg.a.61450DOI Listing
March 2020

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

JAMA 2019 11;322(17):1682-1691

Clayton Eye Care Center Management Inc, Marrow, Georgia.

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.

Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.

Design, Settings, And Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.

Exposures: Genetic variants associated with primary open-angle glaucoma.

Main Outcomes And Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data.

Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.

Conclusions And Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.
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http://dx.doi.org/10.1001/jama.2019.16161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865235PMC
November 2019

Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system.

Pharmacogenet Genomics 2019 10;29(8):192-199

Division of Research, Kaiser Permanente Northern California, Oakland, California.

Objective: To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment.

Methods: A retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996 and 2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin blood concentration, neurologic side effects, and medication dispensing patterns reflecting clinician prescribing practice and patient response.

Results: Among 993 participants, we identified 69% extensive, 20% high-intermediate, 10% low-intermediate, and 2% poor metabolizers based on CYP2C9 genotypes. Compared with extensive metabolizer genotype, low-intermediate/poor metabolizer genotype was associated with increased dose-adjusted phenytoin blood concentration [21.3 pg/mL, 95% confidence interval (CI): 13.6-29.0 pg/mL; P < 0.01] and increased risk of neurologic side effects (hazard ratio: 2.40, 95% CI: 1.24-4.64; P < 0.01). Decreased function CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, although these associations varied by treatment indication for phenytoin.

Conclusion: CYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.
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http://dx.doi.org/10.1097/FPC.0000000000000383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989102PMC
October 2019

Genetic ancestry does not explain increased atopic dermatitis susceptibility or worse disease control among African American subjects in 2 large US cohorts.

J Allergy Clin Immunol 2020 01 29;145(1):192-198.e11. Epub 2019 Jul 29.

Division of Research, Kaiser Permanente, Oakland, Calif.

Background: Atopic dermatitis (AD) is more common among African American children. Whether there are racial/ethnic difference among adults with AD and the causes for those disparities are unclear.

Objective: We sought to examine the relationship between self-reported race/ethnicity and AD and determine whether African genetic ancestry is predictive of these outcomes among African American subjects.

Methods: We analyzed data from 2 independent multiethnic longitudinal studies: 86,893 subjects aged 18 to 100 years from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and 5467 subjects aged 2 to 26 years from the national Pediatric Eczema Elective Registry (PEER) cohort. The primary outcomes were physician-diagnosed AD in GERA and repeated measures of self-reported disease control among patients with physician-diagnosed AD at 6-month intervals in PEER. We examined whether self-identified African American race/ethnicity was predictive of these outcomes and then tested whether a continuous measure of African genetic ancestry was associated with outcomes within the African American group.

Results: AD was more common among self-identified African American subjects than non-Hispanic white subjects in GERA (4.4% vs 2.1%; odds ratio, 2.06; 95% CI, 1.70-2.48) and less well-controlled in PEER subjects (odds of 1-level worse control, 1.91; 95% CI, 1.64-2.22). However, African genetic ancestry was not associated with AD risk or control among self-identified African American subjects in either cohort, nor did an AD polygenic risk score or genetic skin pigment score explain the AD disparities in patients with AD.

Conclusion: Ancestry-related genetic effects do not explain increased AD prevalence or poorer disease control among African American subjects.
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http://dx.doi.org/10.1016/j.jaci.2019.06.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949407PMC
January 2020

Telomere length and socioeconomic status at neighborhood and individual levels among 80,000 adults in the Genetic Epidemiology Research on Adult Health and Aging cohort.

Environ Epidemiol 2019 Jun 1;3(3):e049. Epub 2019 May 1.

Division of Research, Oakland, Kaiser Permanente Northern California, Oakland, California.

Background: Telomere length (TL) may serve as a biologic marker of aging. We examined neighborhood and individual-level socioeconomic status (SES) in relation to TL.

Methods: The study included 84,996 non-Hispanic white subjects from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, part of the Research Program on Genes, Environment and Health. Relative TL (T/S) was log transformed to improve normality and standardized to have mean 0 and variance 1. Neighborhood SES was measured using the Neighborhood Deprivation Index (NDI), and individual SES was measured by self-reported education level. We fit linear regression models of TL on age, sex, smoking, body mass index, comorbidities, NDI, and education level. We tested for differences in the associations by sex and nonlinearity in the association of NDI with TL.

Results: Each SD increase in NDI was associated with a decrease of 0.0192 in standardized TL, 95% confidence interval (CI) = -0.0306, -0.0078. There was no evidence of nonlinearity in the association of NDI with TL. We further found that less than high school education was associated with a decrease of 0.1371 in standardized TL, 95% CI = -0.1919, -0.0823 as compared to a college education. There were no differences in the associations by sex.

Conclusions: We found evidence that both lower neighborhood SES and lower individual-level SES are associated with shorter TL among non-Hispanic whites. Our findings suggest that socioeconomic factors may influence aging by contributing to shorter TL.
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http://dx.doi.org/10.1097/EE9.0000000000000049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939422PMC
June 2019

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Nat Commun 2019 01 22;10(1):376. Epub 2019 Jan 22.

Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, 01246903, SP, Brazil.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
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http://dx.doi.org/10.1038/s41467-018-08008-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342931PMC
January 2019

Characterization of Statin Low-Density Lipoprotein Cholesterol Dose-Response Using Electronic Health Records in a Large Population-Based Cohort.

Circ Genom Precis Med 2018 09;11(9):e002043

Institute for Human Genetics (A.O., T.J.H., N.R.), University of California, San Francisco, CA.

Background: Low-density lipoprotein cholesterol (LDL-C) response to statin therapy has not been fully elucidated in real-world populations. The primary objective of this study was to characterize statin LDL-C dose-response and its heritability in a large, multiethnic population of statin users.

Methods: We determined the effect of statin dosing on lipid measures utilizing electronic health records in 33 139 statin users from the Kaiser Permanente GERA cohort (Genetic Epidemiology Research on Adult Health and Aging). The relationship between statin defined daily dose and lipid parameter response (percent change) was determined.

Results: Defined daily dose and LDL-C response was associated in a log-linear relationship (β, -6.17; SE, 0.09; P<10) which remained significant after adjusting for prespecified covariates (adjusted β, -5.59; SE, 0.12; P<10). Statin type, sex, age, smoking status, diabetes mellitus, and East Asian race/ethnicity were significant independent predictors of statin-induced changes in LDL-C. Based on a variance-component method within the subset of statin users who had at least 1 first-degree relative who was also a statin user (n=1036), heritability of statin LDL-C response was estimated at 11.7% (SE, 8.6%; P=0.087).

Conclusions: Using electronic health record data, we observed a statin LDL-C dose-response consistent with the rule of 6% from prior clinical trial data. Clinical and demographic predictors of statin LDL-C response exhibited highly significant but modest effects. Finally, statin-induced changes in LDL-C were not found to be strongly inherited. Ultimately, these findings demonstrate (1) the utility of electronic health records as a reliable source to generate robust phenotypes for pharmacogenomic research and (2) the potential role of statin precision medicine in lipid management.
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http://dx.doi.org/10.1161/CIRCGEN.117.002043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214660PMC
September 2018

The Clinical Sequencing Evidence-Generating Research Consortium: Integrating Genomic Sequencing in Diverse and Medically Underserved Populations.

Am J Hum Genet 2018 09;103(3):319-327

Department of Biomedical Research, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA.

The Clinical Sequencing Evidence-Generating Research (CSER) consortium, now in its second funding cycle, is investigating the effectiveness of integrating genomic (exome or genome) sequencing into the clinical care of diverse and medically underserved individuals in a variety of healthcare settings and disease states. The consortium comprises a coordinating center, six funded extramural clinical projects, and an ongoing National Human Genome Research Institute (NHGRI) intramural project. Collectively, these projects aim to enroll and sequence over 6,100 participants in four years. At least 60% of participants will be of non-European ancestry or from underserved settings, with the goal of diversifying the populations that are providing an evidence base for genomic medicine. Five of the six clinical projects are enrolling pediatric patients with various phenotypes. One of these five projects is also enrolling couples whose fetus has a structural anomaly, and the sixth project is enrolling adults at risk for hereditary cancer. The ongoing NHGRI intramural project has enrolled primarily healthy adults. Goals of the consortium include assessing the clinical utility of genomic sequencing, exploring medical follow up and cascade testing of relatives, and evaluating patient-provider-laboratory level interactions that influence the use of this technology. The findings from the CSER consortium will offer patients, healthcare systems, and policymakers a clearer understanding of the opportunities and challenges of providing genomic medicine in diverse populations and settings, and contribute evidence toward developing best practices for the delivery of clinically useful and cost-effective genomic sequencing in diverse healthcare settings.
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http://dx.doi.org/10.1016/j.ajhg.2018.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128306PMC
September 2018

A Large Multiethnic Genome-Wide Association Study of Adult Body Mass Index Identifies Novel Loci.

Genetics 2018 10 14;210(2):499-515. Epub 2018 Aug 14.

Division of Research, Kaiser Permanente Northern California, Oakland, California 94612

Body mass index (BMI), a proxy measure for obesity, is determined by both environmental (including ethnicity, age, and sex) and genetic factors, with > 400 BMI-associated loci identified to date. However, the impact, interplay, and underlying biological mechanisms among BMI, environment, genetics, and ancestry are not completely understood. To further examine these relationships, we utilized 427,509 calendar year-averaged BMI measurements from 100,418 adults from the single large multiethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We observed substantial independent ancestry and nationality differences, including ancestry principal component interactions and nonlinear effects. To increase the list of BMI-associated variants before assessing other differences, we conducted a genome-wide association study (GWAS) in GERA, with replication in the Genetic Investigation of Anthropomorphic Traits (GIANT) consortium combined with the UK Biobank (UKB), followed by GWAS in GERA combined with GIANT, with replication in the UKB. We discovered 30 novel independent BMI loci ( < 5.0 × 10) that replicated. We then assessed the proportion of BMI variance explained by sex in the UKB using previously identified loci compared to previously and newly identified loci and found slight increases: from 3.0 to 3.3% for males and from 2.7 to 3.0% for females. Further, the variance explained by previously and newly identified variants decreased with increasing age in the GERA and UKB cohorts, echoed in the variance explained by the entire genome, which also showed gene-age interaction effects. Finally, we conducted a tissue expression QTL enrichment analysis, which revealed that GWAS BMI-associated variants were enriched in the cerebellum, consistent with prior work in humans and mice.
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http://dx.doi.org/10.1534/genetics.118.301479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216593PMC
October 2018

A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.

Nat Commun 2018 06 11;9(1):2278. Epub 2018 Jun 11.

Division of Research, Kaiser Permanente Northern California (KPNC), Oakland, CA, 94612, USA.

Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TMTC2, IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). Functional studies support intraocular pressure-related influences of FMNL2 and LMX1B, with certain Lmx1b mutations causing high IOP and glaucoma resembling POAG in mice. The newly identified loci increase the proportion of variance explained in each GERA race/ethnicity group, with the largest gain in African-Americans (0.5-3.1%). A meta-analysis combining GERA and UKB identifies 24 additional loci. Our study provides important insights into glaucoma pathogenesis.
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http://dx.doi.org/10.1038/s41467-018-04555-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995837PMC
June 2018

Newton E. Morton (1929-2018).

Am J Hum Genet 2018 Jun 8;102(6):1011-1017. Epub 2018 Jun 8.

Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA; Kaiser Permanente Northern California, Division of Research, Oakland, CA 94612, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2018.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175862PMC
June 2018

A large electronic-health-record-based genome-wide study of serum lipids.

Nat Genet 2018 03 5;50(3):401-413. Epub 2018 Mar 5.

Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.

A genome-wide association study (GWAS) of 94,674 ancestrally diverse Kaiser Permanente members using 478,866 longitudinal electronic health record (EHR)-derived measurements for untreated serum lipid levels empowered multiple new findings: 121 new SNP associations (46 primary, 15 conditional, and 60 in meta-analysis with Global Lipids Genetic Consortium data); an increase of 33-42% in variance explained with multiple measurements; sex differences in genetic impact (greater impact in females for LDL, HDL, and total cholesterol and the opposite for triglycerides); differences in variance explained among non-Hispanic whites, Latinos, African Americans, and East Asians; genetic dominance and epistatic interaction, with strong evidence for both at the ABO and FUT2 genes for LDL; and tissue-specific enrichment of GWAS-associated SNPs among liver, adipose, and pancreas eQTLs. Using EHR pharmacy data, both LDL and triglyceride genetic risk scores (477 SNPs) were strongly predictive of age at initiation of lipid-lowering treatment. These findings highlight the value of longitudinal EHRs for identifying new genetic features of cholesterol and lipoprotein metabolism with implications for lipid treatment and risk of coronary heart disease.
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http://dx.doi.org/10.1038/s41588-018-0064-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942247PMC
March 2018
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