Publications by authors named "Catherine Schaefer"

102 Publications

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

Pregnancy does not modify the risk of MS in genetically susceptible women.

Neurol Neuroimmunol Neuroinflamm 2020 11 9;7(6). Epub 2020 Oct 9.

From the Divisions of Epidemiology and Biostatistics (C.J.A., S.L.W.), School of Public Health, University of California, Berkeley, Berkeley, CA; Genetic Epidemiology and Genomics Laboratory (X.S., L.F.B.), University of California, Berkeley, Berkeley, CA; School of Public Health (P.T.B.), University of California, Berkeley, Berkeley, CA, USA; Department of Research & Evaluation (E.G., J.B.S., A.H.X.), Kaiser Permanente Southern California, Los Angeles, CA; Kaiser Permanente Division of Research (K.H.B., T.C., C.S.), Kaiser Permanente Northern California, Oakland, CA; University of Oslo (S.D.B.), Institute of Clinical Medicine & Oslo University Hospital, Department of Neurology, Oslo, Norway; Oslo University Hospital (M.W.-H.), Department of Neurology, Oslo, Norway; Department of Clinical Neuroscience (T.O.), Karolinska Instituet, Stockholm, Sweden; Department of Clinical Neuroscience (I.K.), Karolinska Institutet, Stockholm, Sweden; Southern California Permanente Medical Group/Kaiser Permanente (A.M.L.-G.), Department of Neurology, Los Angeles, CA; and Institute of Environmental Medicine (L.A.), Karolinska Institutet and Centre for Occupational and Environmental Medicine, Region Stockholm, Stockholm, Sweden.

Objective: To use the case-only gene-environment (G [Formula: see text] E) interaction study design to estimate interaction between pregnancy before onset of MS symptoms and established genetic risk factors for MS among White adult females.

Methods: We studied 2,497 female MS cases from 4 cohorts in the United States, Sweden, and Norway with clinical, reproductive, and genetic data. Pregnancy exposure was defined in 2 ways: (1) [Formula: see text] live birth pregnancy before onset of MS symptoms and (2) parity before onset of MS symptoms. We estimated interaction between pregnancy exposure and established genetic risk variants, including a weighted genetic risk score and both HLA and non-HLA variants, using logistic regression and proportional odds regression within each cohort. Within-cohort associations were combined using inverse variance meta-analyses with random effects. The case-only G × E independence assumption was tested in 7,067 individuals without MS.

Results: Evidence for interaction between pregnancy exposure and established genetic risk variants, including the strongly associated allele and a weighted genetic risk score, was not observed. Results from sensitivity analyses were consistent with observed results.

Conclusion: Our findings indicate that pregnancy before symptom onset does not modify the risk of MS in genetically susceptible White females.
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http://dx.doi.org/10.1212/NXI.0000000000000898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673284PMC
November 2020

A validation study for remote testing of cognitive function in multiple sclerosis.

Mult Scler 2021 04 14;27(5):795-798. Epub 2020 Jul 14.

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

Objectives: Determine the validity and reliability of a remote, technician-guided cognitive assessment for multiple sclerosis (MS), incorporating the Symbol Digit Modalities Test (SDMT) and the California Verbal Learning Test, Second Edition (CVLT-II).

Methods: In 100 patients, we compared conventional in-person testing to remote, web-assisted assessments, and in 36 patients, we assessed test-retest reliability using two equivalent, alternative forms.

Results: In-person and remote-administered SDMT ( = 0.85) and CVLT-II ( = 0.71) results were very similar. Reliability was adequate and alternative forms of SDMT ( = 0.92) and CVLT-II ( = 0.81) produced similar results.

Conclusions: Findings indicate remote assessment can provide valid, reliable measures of cognitive function in MS.
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http://dx.doi.org/10.1177/1352458520937385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854963PMC
April 2021

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

Associations of CYP2C9 and CYP2C19 Pharmacogenetic Variation with Phenytoin-Induced Cutaneous Adverse Drug Reactions.

Clin Transl Sci 2020 09 18;13(5):1004-1009. Epub 2020 Apr 18.

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

The role of cytochrome P450 (CYP)2C9 and CYP2C19 genetic variation in risk for phenytoin-induced cutaneous adverse drug events is not well understood independently of the human leukocyte antigen B (HLA-B)*15:02 risk allele. In the multi-ethnic resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we identified 382 participants who filled a phenytoin prescription between 2005 and 2017. These participants included 21 people (5%) who self-identified as Asian, 18 (5%) as black, 29 (8%) as white Hispanic, and 308 (81%) as white non-Hispanic. We identified 264 (69%) CYP2C9*1/*1, 77 (20%) CYP2C9*1/*2, and 29 (8%) CYP2C9*1/*3. We also determined CYP2C19 genotypes, including 112 with the increased activity CYP2C19*17 allele. Using electronic clinical notes, we identified 32 participants (8%) with phenytoin-induced cutaneous adverse events recorded within 100 days of first phenytoin dispensing. Adjusting for age, sex, daily dose, and race/ethnicity, participants with CYP2C9*1/*3 or CYP2C9*2/*2 genotypes were more likely to develop cutaneous adverse events compared with CYP2C9*1/*1 participants (odds ratio 4.47; 95% confidence interval 1.64-11.69; P < 0.01). Among participants with low-intermediate and poor CYP2C9 metabolizer genotypes, eight (22%) who also had extensive and rapid CYP2C19 metabolizer genotypes experienced cutaneous adverse events, compared with none of those who also had intermediate CYP2C19 metabolizer genotypes (P = 0.17). Genetic variation reducing CYP2C9 metabolic activity may increase risk for phenytoin-induced cutaneous adverse events in the absence of the HLA-B*15:02 risk allele.
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http://dx.doi.org/10.1111/cts.12787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485959PMC
September 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

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

Maternal cortisol during pregnancy and offspring schizophrenia: Influence of fetal sex and timing of exposure.

Schizophr Res 2019 11 22;213:15-22. Epub 2019 Jul 22.

Department of Epidemiology, Columbia University Mailman School of Public Health, 722 West 168(th) Street, New York, NY 10032, United States of America; New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, United States of America; Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, United States of America. Electronic address:

Introduction: Maternal stress during pregnancy has been repeatedly linked to increased risk for schizophrenia; however, no study has examined maternal cortisol during pregnancy and risk for the disorder. Study aims were to determine whether prenatal cortisol was associated with risk for schizophrenia and risk for an intermediate phenotype-decreased fetal growth-previously linked to prenatal cortisol and schizophrenia. Timing of exposure and fetal sex also were examined given previous findings.

Methods: Participants were 64 cases diagnosed with schizophrenia spectrum disorders (SSD) and 117 controls from a prospective birth cohort study. Maternal cortisol was determined from stored sera from each trimester and psychiatric diagnoses were assessed from offspring using semi-structured interviews and medical records review.

Results: Maternal cortisol during pregnancy was not associated with risk for offspring schizophrenia. There was a significant interaction between 3rd trimester cortisol and case status on fetal growth. Specifically, cases exposed to higher 3rd trimester maternal cortisol had significantly decreased fetal growth compared to controls. In addition, these findings were restricted to male offspring.

Conclusions: Our results indicate that higher prenatal cortisol is associated with an intermediate phenotype linked to schizophrenia, fetal growth, but only among male offspring who developed schizophrenia. Findings were consistent with evidence that schizophrenia genes may disrupt placental functioning specifically for male fetuses, as well as findings that males are more vulnerable to maternal cortisol during pregnancy. Finally, results suggest that examining fetal sex and intermediate phenotypes may be important in understanding the mechanisms involved in prenatal contributors to schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2019.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074891PMC
November 2019

miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS.

Ann Clin Transl Neurol 2019 Jun 15;6(6):1053-1061. Epub 2019 May 15.

Department of Neurology University of California San Francisco California.

Objective: Onset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped-MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped-MS than in adult-onset MS. This study aimed to look for evidence of miRNA involvement in ped-MS pathogenesis.

Methods: GWAS results from 486 ped-MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR-SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes.

Results: MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS ( = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling.

Interpretation: Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.
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http://dx.doi.org/10.1002/acn3.786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562070PMC
June 2019

Multiple Stakeholder Views on Data Sharing in a Biobank in an Integrated Healthcare Delivery System: Implications for Biobank Governance.

Public Health Genomics 2018 5;21(5-6):207-216. Epub 2019 Jun 5.

Institute for Health and Aging, University of California, San Francisco, San Francisco, California, USA,

Background: Beginning in 2005, researchers at Kaiser Permanente Northern California (KPNC) Division of Research developed the Research Program on Genes, Environment, and Health (RPGEH), a research resource of linked biospecimens, health surveys, and electronic health records on more than 200,000 adult KPNC members. This study examined multiple stakeholders' values and preferences regarding protection of participants' privacy and wide sharing of participant data by RPGEH.

Methods: We conducted 45 semi-structured interviews in person or via phone and two focus groups with seven stakeholder groups, including RPGEH participants and decliners who are KPNC members, KPNC research scientists, external scientists, leadership, Human Subjects Research Protection Program staff, and RPGEH Community Advisory Panel members.

Results: Three major themes emerged related to: (1) perceived individual and social harms associated with data sharing; (2) concerns to address when governing access to RPGEH data; and (3) impact of a blurred boundary between research and clinical care in the context of biobanking.

Conclusions: The study results were considered in the development of RPGEH data governance and motivated the inclusion of KPNC Community Advisory Panel members and ELSI experts on committees that evaluate data access proposals. Our findings can help inform other biobanks going through similar processes developing data sharing and access policies.
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http://dx.doi.org/10.1159/000500442DOI Listing
June 2019

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

Experimental Paradigm for Measuring the Effects of Self-distancing in Young Children.

J Vis Exp 2019 03 1(145). Epub 2019 Mar 1.

Insitute of Child Development, University of Minnesota-Twin Cities.

Self-distancing (i.e., creating mental distance between the self and a stimulus by adopting a less egocentric perspective) has been studied as a way to improve adolescents' and adults' emotion regulation. These studies instruct adolescents and adults to use visual imagery or language to create distance from the self before engaging in self-regulation tasks and when thinking about past and future events. For example, adults are asked to recall past, negative emotional experiences from either a first-person perspective (no distance) or a third-person perspective (self-distanced). These studies show that a self-distanced perspective allows adults to cope more adaptively when recalling negative feelings. However, the self-distancing paradigm used with adults was not developmentally appropriate for young children. This modified self-distancing paradigm involves instructing children to think about their thoughts, feelings, and actions from different perspectives that vary in their distance from the self while completing a self-regulation task. The paradigm involves randomly assigning children to use one of three perspectives: self-immersed, third-person, or exemplar. In the self-immersed condition, children are asked to think about themselves using the first-person perspective (e.g., "How am I feeling?") and no distance is created from the self. In the third-person condition, children are asked to create distance from the self by using the third-person perspective (e.g., "How is [child's name] feeling?"). In the exemplar condition, the greatest distance from the self is created by asking children to pretend to be a media character and to think about that character's thoughts and feelings (e.g., "How is Batman feeling?"). Studies using the self-distancing paradigm with 4-6-year-olds have found that as the amount of distance from the self increases (self-immersed < third-person < exemplar), children perform better on self-regulation tasks. These findings suggest that the strategies implemented in the self-distancing protocol may be useful to include in self-regulation interventions for young children.
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http://dx.doi.org/10.3791/59056DOI Listing
March 2019

The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies.

Int J Cancer 2019 12 4;145(12):3244-3256. Epub 2019 Apr 4.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.
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http://dx.doi.org/10.1002/ijc.32276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745281PMC
December 2019

Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry.

PLoS Genet 2019 01 17;15(1):e1007808. Epub 2019 Jan 17.

Kaiser Permanente Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America.

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.
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http://dx.doi.org/10.1371/journal.pgen.1007808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353231PMC
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

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

Individual differences in the effectiveness of self-distancing for young children's emotion regulation.

Br J Dev Psychol 2019 03 15;37(1):84-100. Epub 2018 Jul 15.

Institute of Child Development, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.

Self-distancing has been shown to improve children's self-regulation in a variety of tasks. However, it is unknown whether this strategy is more effective for some children than others. This study investigated self-distancing in relation to individual differences in executive function (EF) and effortful control (EC). Typically developing 4- (n = 72) and 6-year-olds (n = 67) were randomly assigned to think about the self from one of four perspectives: self-immersed, control, third-person, or competent media character. Children participated in a frustrating task for up to 10 min and overt expressions of frustration were coded. Conceptually replicating prior research with adults, younger children, and children with lower EF and lower EC (independent of age) benefitted the most from self-distancing. This suggests self-distancing is especially effective during a frustrating task for children with less developed self-control, adding to a growing body of research showing self-distancing is especially effective for vulnerable individuals. Statement of contribution What is already known on this subject? Using third-person speech and pretending to be a media character improve children's self-regulation. Age and theory of mind skills are related to the effectiveness of self-distancing. What does this study add? Self-distancing can help children regulate their emotions during an emotionally charged task. Individual differences in executive function and effortful control are related to the efficacy of self-distancing.
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http://dx.doi.org/10.1111/bjdp.12259DOI Listing
March 2019

Incorporating machine learning approaches to assess putative environmental risk factors for multiple sclerosis.

Mult Scler Relat Disord 2018 Aug 23;24:135-141. Epub 2018 Jun 23.

University of California, Berkeley, CA, USA.

Background: Multiple sclerosis (MS) incidence has increased recently, particularly in women, suggesting a possible role of one or more environmental exposures in MS risk. The study objective was to determine if animal, dietary, recreational, or occupational exposures are associated with MS risk.

Methods: Least absolute shrinkage and selection operator (LASSO) regression was used to identify a subset of exposures with potential relevance to disease in a large population-based (Kaiser Permanente Northern California [KPNC]) case-control study. Variables with non-zero coefficients were analyzed in matched conditional logistic regression analyses, adjusted for established environmental risk factors and socioeconomic status (if relevant in univariate screening),± genetic risk factors, in the KPNC cohort and, for purposes of replication, separately in the Swedish Epidemiological Investigation of MS cohort. These variables were also assessed in models stratified by HLA-DRB1*15:01 status since interactions between risk factors and that haplotype have been described.

Results: There was a suggestive association of pesticide exposure with having MS among men, but only in those who were positive for HLA-DRB1*15:01 (OR pooled = 3.11, 95% CI 0.87, 11.16, p = 0.08).

Conclusions: While this finding requires confirmation, it is interesting given the association between pesticide exposure and other neurological diseases. The study also demonstrates the application of LASSO to identify environmental exposures with reduced multiple statistical testing penalty. Machine learning approaches may be useful for future investigations of concomitant MS risk or prognostic factors.
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http://dx.doi.org/10.1016/j.msard.2018.06.009DOI Listing
August 2018

Cohort effects in children's delay of gratification.

Dev Psychol 2018 08 25;54(8):1395-1407. Epub 2018 Jun 25.

Department of Psychology, Columbia University.

In the 1960s at Stanford University's Bing Preschool, children were given the option of taking an immediate, smaller reward or receiving a delayed, larger reward by waiting until the experimenter returned. Since then, the "Marshmallow Test" has been used in numerous studies to assess delay of gratification. Yet, no prior study has compared the performance of children across the decades. Common wisdom suggests children today would wait less long, preferring immediate gratification. Study 1 confirmed this intuition in a survey of adults in the United States (N = 354; Mdn age = 34 years). To test the validity of this prediction, Study 2 analyzed the original data for average delay-of-gratification times (out of 10 min) of 840 typically developing U.S. children in three birth cohorts from similar middle-high socioeconomic backgrounds in the late 1960s, 1980s, and 2000s, matched on age (3 to 5 years) at the time of testing. In contrast to popular belief, results revealed a linear increase in delay over time (p < .0001, ηp2 = .047), such that children in the 2000s waited on average 2 min longer than children in the 1960s, and 1 min longer than children in the 1980s. This pattern was robust with respect to age, sex, geography and sampling effects. We posit that increases in symbolic thought, technology, preschool education, and public attention to executive function skills have contributed to this finding, but caution that more research in diverse populations is needed to examine the generality of the findings and to identify causal factors. (PsycINFO Database Record
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http://dx.doi.org/10.1037/dev0000533DOI Listing
August 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

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

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

Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men.

PLoS One 2017 27;12(12):e0187741. Epub 2017 Dec 27.

Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu, HI, United States of America.

Introduction: Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease-risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin.

Methods: Statistical analyses of individual participant data from 12,330 male controls aged 25-85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates.

Results: Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones.

Conclusion: Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187741PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744924PMC
January 2018
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