Publications by authors named "Jennifer Wessel"

53 Publications

Barriers to Weight Management Among Overweight and Obese Firefighters.

J Occup Environ Med 2020 01;62(1):37-45

Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University (Ms Muegge, Dr Zollinger, Dr Song, Dr Wessel); Department of Biostatistics, School of Medicine, Indiana University (Dr Monahan); National Institute for Public Safety Health (Ms Muegge, Dr Moffatt), Indianapolis, Indiana.

Objective: To examine barriers to weight management among firefighters.

Methods: Health risk data collected on 2373 overweight firefighters were used for this cross-sectional study. Barriers to weight management were the dependent variables and demographic characteristics, readiness for change, and health risk factors were the correlates in the multivariate-adjusted logistic models.

Results: Overweight firefighters who were ready to begin a weight management program were more likely to identify "lack of knowledge about weight management," "lack of access to exercise opportunities," and "eating helps me cope with stress" and report a greater number of barriers toward weight management. Older firefighters were less likely to identify or report one or more barriers to weight management.

Conclusion: Understanding barriers, readiness for change, and age may be useful in planning interventions to help firefighters better manage their weight.
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http://dx.doi.org/10.1097/JOM.0000000000001751DOI Listing
January 2020

Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.

Am J Hum Genet 2019 10 26;105(4):706-718. Epub 2019 Sep 26.

National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham MA 01702, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.
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http://dx.doi.org/10.1016/j.ajhg.2019.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817529PMC
October 2019

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Nature 2019 06 22;570(7759):71-76. Epub 2019 May 22.

Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, South Korea.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10) and candidate genes from knockout mice (P = 5.2 × 10). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
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http://dx.doi.org/10.1038/s41586-019-1231-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699738PMC
June 2019

The Continuing Evolution of Precision Health in Type 2 Diabetes: Achievements and Challenges.

Curr Diab Rep 2019 02 26;19(4):16. Epub 2019 Feb 26.

Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.

Purpose Of Review: The purpose of this review was to summarize recent advances in the genomics of type 2 diabetes (T2D) and to highlight current initiatives to advance precision health.

Recent Findings: Generation of multi-omic data to measure each of the "biologic layers," developments in describing genomic function and annotation in T2D relevant tissue, along with the increasing recognition that T2D is a heterogeneous disease, and large-scale collaborations have all contributed to advancing our understanding of the molecular basis of T2D. Substantial advances have been made in understanding the molecular basis of T2D pathogenesis, such that precision health diabetes is increasingly becoming a reality. For precision diabetes to become a routine in clinical and public health, additional large-scale multi-omic initiatives are needed along with better assessment of our environment to delineate an individual's diabetes subtype for improved detection and management.
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http://dx.doi.org/10.1007/s11892-019-1137-2DOI Listing
February 2019

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Nat Genet 2019 03 18;51(3):452-469. Epub 2019 Feb 18.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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http://dx.doi.org/10.1038/s41588-018-0334-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560635PMC
March 2019

Maternal lipid profile differs by gestational diabetes physiologic subtype.

Metabolism 2019 02 20;91:39-42. Epub 2018 Nov 20.

Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA, USA; Centre de Recherche du Centre hospitalier universitaire de Sherbrooke (CHUS), Québec, Canada; Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address:

Aim: To characterize lipid profiles in women with different gestational diabetes mellitus (GDM) physiologic subtypes.

Methods: We measured seven lipid markers (total cholesterol, LDL, HDL, triglycerides, non-esterified fatty acids (NEFA), ApoA, ApoB) in fasting plasma collected in a prospective cohort of 805 pregnant women during second trimester. We estimated insulin sensitivity and secretion using oral glucose tolerance test-based validated indices. We categorized GDM physiologic subtypes by insulin sensitivity and secretion defects defined as values below the 25th percentile among women with normal glucose tolerance (NGT), as previously established. We compared lipid markers across NGT and GDM subtypes. We explored associations between lipid markers and newborn anthropometry in the overall group and stratified by glucose tolerance status.

Results: Among 805 women, 67 (8.3%) developed GDM. Women with GDM had higher body mass index (BMI; 29.3 vs. 26.6 kg/m), while ethnicity (97.3% vs. 97.0% European ancestry) and age (28 vs. 29 years) were similar. In comparison to women with NGT, women with GDM characterized by a predominant insulin sensitivity defect had significantly higher triglycerides (2.20 vs. 1.82, P = 0.002), lower HDL (1.64 vs. 1.90, P = 0.01) and higher NEFA (0.34 vs. 0.24, P < 0.0001). GDM women with a predominant insulin secretion defect differed from women with NGT with respect to NEFA (0.32 vs. 0.24, P = 0.003) while other lipid markers were similar. These associations remained significant after adjusting for maternal age and BMI. Greater maternal levels of NEFA were associated with higher birth weight z-scores in women with an insulin secretion defect (BMI-adjusted r = 0.58, P = 0.01). We did not find significant associations between other lipid markers and newborn anthropometry in other groups.

Conclusion: Women with GDM have distinct lipid profiles based on their GDM physiologic subtype which may not be apparent when investigating GDM as a single group.
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http://dx.doi.org/10.1016/j.metabol.2018.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058811PMC
February 2019

Excess mortality among Indiana firefighters, 1985-2013.

Am J Ind Med 2018 12 13;61(12):961-967. Epub 2018 Nov 13.

National Institute for Public Safety Health, Indianapolis, Indiana.

Background: Firefighters are exposed to toxic agents increasing their risk for cancer and cardiovascular disease. We examined the odds of cancer and cardiovascular mortality of firefighters relative to a matched group of non-firefighters from the general population.

Methods: Firefighter death records were matched to four non-firefighter death records on age at time of death, sex, race, ethnicity, and year of death. Exact odds ratios, 95% confidence intervals, and P-values were calculated using conditional logistic regression to compare groups.

Results: The odds of death due to malignant cancers was significantly higher for firefighters than non-firefighters (OR: 1.19; 95%CI 1.08, 1.30). There was no difference in the odds of death for cardiovascular diseases, including ischemic heart disease, between the two groups.

Conclusions: The study suggests the importance of early and effective cancer prevention strategies among firefighters including worksite health promotion programs and incumbent physical activity evaluation.
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http://dx.doi.org/10.1002/ajim.22918DOI Listing
December 2018

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

Nat Genet 2018 04 9;50(4):559-571. Epub 2018 Apr 9.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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http://dx.doi.org/10.1038/s41588-018-0084-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898373PMC
April 2018

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 05;50(5):766-767

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41588-018-0082-3DOI Listing
May 2018

Type 2 Diabetes Genetic Risk Scores Are Associated With Increased Type 2 Diabetes Risk Among African Americans by Cardiometabolic Status.

Clin Med Insights Endocrinol Diabetes 2018 3;11:1179551417748942. Epub 2018 Jan 3.

Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.

The relationship between genetic risk variants associated with glucose homeostasis and type 2 diabetes risk has yet to be fully explored in African American populations. We pooled data from 4 prospective studies including 4622 African Americans to assess whether β-cell dysfunction (BCD) and/or insulin resistance (IR) genetic variants were associated with increased type 2 diabetes risk. The BCD genetic risk score (GRS) and combined BCD/IR GRS were significantly associated with increased type 2 diabetes risk. In cardiometabolic-stratified models, the BCD and IR GRS were associated with increased type 2 diabetes risk among 5 cardiometabolic strata: 3 clinically healthy strata and 2 clinically unhealthy strata. Genetic risk scores related to BCD and IR were associated with increased risk of type 2 diabetes in African Americans. Notably, the GRSs were significant predictors of type 2 diabetes among individuals in clinically normal ranges of cardiometabolic traits.
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http://dx.doi.org/10.1177/1179551417748942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757425PMC
January 2018

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 01 22;50(1):26-41. Epub 2017 Dec 22.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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http://dx.doi.org/10.1038/s41588-017-0011-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945951PMC
January 2018

Exome-wide association study of plasma lipids in >300,000 individuals.

Nat Genet 2017 Dec 30;49(12):1758-1766. Epub 2017 Oct 30.

Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
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http://dx.doi.org/10.1038/ng.3977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709146PMC
December 2017

Clinical characteristics and 12-month outcomes of patients with valvular and non-valvular atrial fibrillation in Kenya.

PLoS One 2017 21;12(9):e0185204. Epub 2017 Sep 21.

Department of Medicine, Duke Clinical Research Institute and Duke Global Health Institute, Duke University, Durham, NC, United States of America.

Background: Atrial fibrillation (AF) is a major contributor to the global cardiovascular disease burden. The clinical profile and outcomes of AF patients with valvular heart diseases in sub-Saharan Africa (SSA) have not been adequately described. We assessed clinical features and 12-month outcomes of patients with valvular AF (vAF) in comparison to AF patients without valvular heart disease (nvAF) in western Kenya.

Methods: We performed a cohort study with retrospective data gathering to characterize risk factors and prospective data collection to characterize their hospitalization, stroke and mortality rates.

Results: The AF patients included 77 with vAF and 69 with nvAF. The mean (SD) age of vAF and nvAF patients were 37.9(14.5) and 69.4(12.3) years, respectively. There were significant differences (p<0.001) between vAF and nvAF patients with respect to female sex (78% vs. 55%), rates of hypertension (29% vs. 73%) and heart failure (10% vs. 49%). vAF patients were more likely to be taking anticoagulation therapy compared to those with nvAF (97% vs. 76%; p<0.01). After 12-months of follow-up, the overall mortality, hospitalization and stroke rates for vAF patients were high, at 10%, 34% and 5% respectively, and were similar to the rates in the nvAF patients (15%, 36%, and 5%, respectively).

Conclusion: Despite younger age and few comorbid conditions, patients with vAF in this developing country setting are at high risk for nonfatal and fatal outcomes, and are in need of interventions to improve short and long-term outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185204PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608343PMC
October 2017

Methodological Standards for Meta-Analyses and Qualitative Systematic Reviews of Cardiac Prevention and Treatment Studies: A Scientific Statement From the American Heart Association.

Circulation 2017 Sep 7;136(10):e172-e194. Epub 2017 Aug 7.

Meta-analyses are becoming increasingly popular, especially in the fields of cardiovascular disease prevention and treatment. They are often considered to be a reliable source of evidence for making healthcare decisions. Unfortunately, problems among meta-analyses such as the misapplication and misinterpretation of statistical methods and tests are long-standing and widespread. The purposes of this statement are to review key steps in the development of a meta-analysis and to provide recommendations that will be useful for carrying out meta-analyses and for readers and journal editors, who must interpret the findings and gauge methodological quality. To make the statement practical and accessible, detailed descriptions of statistical methods have been omitted. Based on a survey of cardiovascular meta-analyses, published literature on methodology, expert consultation, and consensus among the writing group, key recommendations are provided. Recommendations reinforce several current practices, including protocol registration; comprehensive search strategies; methods for data extraction and abstraction; methods for identifying, measuring, and dealing with heterogeneity; and statistical methods for pooling results. Other practices should be discontinued, including the use of levels of evidence and evidence hierarchies to gauge the value and impact of different study designs (including meta-analyses) and the use of structured tools to assess the quality of studies to be included in a meta-analysis. We also recommend choosing a pooling model for conventional meta-analyses (fixed effect or random effects) on the basis of clinical and methodological similarities among studies to be included, rather than the results of a test for statistical heterogeneity.
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http://dx.doi.org/10.1161/CIR.0000000000000523DOI Listing
September 2017

Disclosing a disability: Do strategy type and onset controllability make a difference?

J Appl Psychol 2017 Sep 17;102(9):1375-1383. Epub 2017 Apr 17.

Sauder School of Business, University of British Columbia.

In hiring contexts, individuals with concealable disabilities make decisions about how they should disclose their disability to overcome observers' biases. Previous research has investigated the effectiveness of binary disclosure decisions-that is, to disclose or conceal a disability-but we know little about how, why, or under what conditions different types of disclosure strategies impact observers' hiring intentions. In this article, we examine disability onset controllability (i.e., whether the applicant is seen as responsible for their disability onset) as a boundary condition for how disclosure strategy type influences the affective reactions (i.e., pity, admiration) that underlie observers' hiring intentions. Across 2 experiments, we found that when applicants are seen as responsible for their disability, strategies that de-emphasize the disability (rather than embrace it) lower observers' hiring intentions by elevating their pity reactions. Thus, the effectiveness of different types of disability disclosure strategies differs as a function of onset controllability. We discuss implications for theory and practice for individuals with disabilities and organizations. (PsycINFO Database Record
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http://dx.doi.org/10.1037/apl0000230DOI Listing
September 2017

A Low-Frequency Inactivating Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

Diabetes 2017 07 24;66(7):2019-2032. Epub 2017 Mar 24.

Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Malmö, Sweden.

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of .
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http://dx.doi.org/10.2337/db16-1329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482074PMC
July 2017

Rare and low-frequency coding variants alter human adult height.

Nature 2017 02 1;542(7640):186-190. Epub 2017 Feb 1.

Netherlands Comprehensive Cancer Organisation, Utrecht, 3501 DB, The Netherlands.

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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http://dx.doi.org/10.1038/nature21039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302847PMC
February 2017

and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

J Am Soc Nephrol 2017 Mar 5;28(3):981-994. Epub 2016 Dec 5.

Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7×10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4×10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
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http://dx.doi.org/10.1681/ASN.2016020131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328154PMC
March 2017

A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.

Sci Transl Med 2016 06;8(341):341ra76

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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http://dx.doi.org/10.1126/scitranslmed.aad3744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5219001PMC
June 2016

Do Genes Determine Our Health? Implications for Designing Lifestyle Interventions and Drug Trials.

Circ Cardiovasc Genet 2016 Feb;9(1):2-3

From the Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis (J.W.); and Department of Medicine, Indiana University School of Medicine, Indianapolis (J.W., D.M.).

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http://dx.doi.org/10.1161/CIRCGENETICS.116.001367DOI Listing
February 2016

A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans.

BMC Endocr Disord 2016 Jan 28;16. Epub 2016 Jan 28.

Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.

Background: Experiments in mice initially suggested a role for the protein angiopoietin-like 8 (ANGPTL8) in glucose homeostasis. However, subsequent experiments in model systems have challenged this proposed role. We sought to better understand the importance of ANGPTL8 in human glucose homeostasis by examining the association of a null mutation in ANGPTL8 with fasting glucose levels and risk for type 2 diabetes.

Methods: A naturally-occurring null mutation in human ANGPTL8 (rs145464906; c.361C > T; p.Q121X) is carried by ~1 in 1000 individuals of European ancestry and is associated with higher levels of plasma high-density lipoprotein cholesterol, suggesting that this mutation has functional significance. We examined the association of p.Q121X with fasting glucose levels and risk for type 2 diabetes in up to 95,558 individuals (14,824 type 2 diabetics and 80,734 controls).

Results: We found no significant association of p.Q121X with either fasting glucose or type 2 diabetes (p-value = 0.90 and 0.65, respectively). Given our sample sizes, we had >98 % power to detect at least a 0.23 mmol/L effect on plasma glucose and >95 % power to detect a 70 % increase in risk for type 2 diabetes.

Conclusion: Disruption of ANGPTL8 function in humans does not seem to have a large effect on measures of glucose tolerance.
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http://dx.doi.org/10.1186/s12902-016-0088-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730725PMC
January 2016

Factors Motivating Individuals to Consider Genetic Testing for Type 2 Diabetes Risk Prediction.

PLoS One 2016 20;11(1):e0147071. Epub 2016 Jan 20.

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.

The purpose of this study was to identify attitudes and perceptions of willingness to participate in genetic testing for type 2 diabetes (T2D) risk prediction in the general population. Adults (n = 598) were surveyed on attitudes about utilizing genetic testing to predict future risk of T2D. Participants were recruited from public libraries (53%), online registry (37%) and a safety net hospital emergency department (10%). Respondents were 37 ± 11 years old, primarily White (54%), female (69%), college educated (46%), with an annual income ≥$25,000 (56%). Half of participants were interested in genetic testing for T2D (52%) and 81% agreed/strongly agreed genetic testing should be available to the public. Only 57% of individuals knew T2D is preventable. A multivariate model to predict interest in genetic testing was adjusted for age, gender, recruitment location and BMI; significant predictors were motivation (high perceived personal risk of T2D [OR = 4.38 (1.76, 10.9)]; family history [OR = 2.56 (1.46, 4.48)]; desire to know risk prior to disease onset [OR = 3.25 (1.94, 5.42)]; and knowing T2D is preventable [OR = 2.11 (1.24, 3.60)], intention (if the cost is free [OR = 10.2 (4.27, 24.6)]; and learning T2D is preventable [OR = 5.18 (1.95, 13.7)]) and trust of genetic testing results [OR = 0.03 (0.003, 0.30)]. Individuals are interested in genetic testing for T2D risk which offers unique information that is personalized. Financial accessibility, validity of the test and availability of diabetes prevention programs were identified as predictors of interest in T2D testing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147071PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720283PMC
July 2016

The long road to employment: Incivility experienced by job seekers.

J Appl Psychol 2016 Mar 5;101(3):333-49. Epub 2015 Oct 5.

Department of Psychology, University of Maryland.

This study addresses how job seekers' experiences of rude and discourteous treatment--incivility--can adversely affect self-regulatory processes underlying job searching. Using the social-cognitive model (Zimmerman, 2000), we integrate social-cognitive theory with the goal orientation literature to examine how job search self-efficacy mediates the relationship between incivility and job search behaviors and how individual differences in learning goal orientation and avoid-performance goal orientation moderate that process. We conducted 3 studies with diverse methods and samples. Study 1 employed a mixed-method design to understand the nature of incivility within the job search context and highlight the role of attributions in linking incivility to subsequent job search motivation and behavior. We tested our hypotheses in Study 2 and 3 employing time-lagged research designs with unemployed job seekers and new labor market entrants. Across both Study 2 and 3 we found evidence that the negative effect of incivility on job search self-efficacy and subsequent job search behaviors are stronger for individuals low, rather than high, in avoid-performance goal orientation. Theoretical implications of our findings and practical recommendations for how to address the influence of incivility on job seeking are discussed.
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http://dx.doi.org/10.1037/apl0000055DOI Listing
March 2016

Genetic mutations in African patients with atrial fibrillation: Rationale and design of the Study of Genetics of Atrial Fibrillation in an African Population (SIGNAL).

Am Heart J 2015 Sep 14;170(3):455-64.e5. Epub 2015 Jun 14.

AMPATH Partnership, Eldoret, Kenya; Department of Medicine, Indiana University, Indianapolis, IN; Department of Medicine, School of Medicine, College of Health Sciences, Moi University, Eldoret, Kenya.

Background: There is an urgent need to understand genetic associations with atrial fibrillation in ethnically diverse populations. There are no such data from sub-Saharan Africa, despite the fact that atrial fibrillation is one of the fastest growing diseases. Moreover, patients with valvular heart disease are underrepresented in studies of the genetics of atrial fibrillation.

Methods: We designed a case-control study of patients with and without a history of atrial fibrillation in Kenya. Cases with atrial fibrillation included those with and without valvular heart disease. Patients underwent clinical phenotyping and will have laboratory analysis and genetic testing of >240 candidate genes associated with cardiovascular diseases. A 12-month follow-up assessment will determine the groups' morbidity and mortality. The primary analyses will describe genetic and phenotypic associations with atrial fibrillation.

Results: We recruited 298 participants: 72 (24%) with nonvalvular atrial fibrillation, 78 (26%) with valvular atrial fibrillation, and 148 (50%) controls without atrial fibrillation. The mean age of cases and controls were 53 and 48 years, respectively. Most (69%) participants were female. Controls more often had hypertension (45%) than did those with valvular atrial fibrillation (27%). Diabetes and current tobacco smoking were uncommon. A history of stroke was present in 25% of cases and in 5% of controls.

Conclusion: This is the first study determining genetic associations in valvular and nonvalvular atrial fibrillation in sub-Saharan Africa with a control population. The results advance knowledge about atrial fibrillation and will enhance international efforts to decrease atrial fibrillation-related morbidity.
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http://dx.doi.org/10.1016/j.ahj.2015.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575772PMC
September 2015

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

Nat Commun 2015 Jan 29;6:5897. Epub 2015 Jan 29.

1] The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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http://dx.doi.org/10.1038/ncomms6897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311266PMC
January 2015

Genetic Testing and Type 2 Diabetes Risk Awareness.

Diabetes Educ 2014 07 19;40(4):427-433. Epub 2014 Mar 19.

School of Medicine, Indiana University, Indianapolis, IN, USA (Dr de Groot, Dr Wessel).

Purpose: The purpose of this study was to examine the motivational, attitudinal, and behavioral predictors of interest in genetic testing (GT) in those with and without awareness of their risk for type 2 diabetes (T2DM).

Methods: A convenience sample of adults visiting emergency departments, libraries, or an online research registry was surveyed. Responses from adults without diabetes who reported 1 or more risk factors for T2DM (eg, family history, body mass index > 25) were included in the analyses (n = 265).

Results: Participants were 37 ± 11 years old, white (54%), and female (69%), with some college education (53%) and an annual income below $25 000 (44%). Approximately half (52%) expressed interest in GT for T2DM. Individuals were stratified by perceived risk for T2DM (risk aware or risk unaware). Among the risk aware, younger age (P < .04) predicted greater interest in GT. Among the risk unaware, family history of T2DM (P < .008) and preference to know genetic risk (P < .0002) predicted interest in GT. Both groups identified the need for low-cost GT.

Conclusions: GT is an increasingly available and accurate tool to predict T2DM risk for patients. In this sample, GT was a salient tool for those with and without awareness of their T2DM risk. Financial accessibility is critical to use of this tool for both groups.
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http://dx.doi.org/10.1177/0145721714527643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4474775PMC
July 2014

Environmental and genetic contributions to indicators of oral malodor in twins.

Twin Res Hum Genet 2011 Dec;14(6):568-72

New York University College of Dentistry, 345 East 24th Street, Room 1005, New York, NY 10010, USA.

This study aimed to: (1) determine concordance rates of self-reported and subjectively determined indicators of oral malodor in twins; (2) determine the relative contributions of genetic and environmental factors to levels of volatile sulfur compounds (VSCs) in intraoral and exhaled breath. Fifty-one twin pairs participated in the study. Measurements of VSCs were obtained by a halimeter. The presence of tongue coatings was determined and twins filled out a 32-item questionnaire on oral malodor indicators independently of one another. Estimates of heritability (h2) for halimeter measurements were computed by SOLAR. The concordance rates for the presence of tongue coating among identical and fraternal twins were 67% and 11%, respectively. In the 10 most informative items, 70% exhibited higher concordance rates for identical than for fraternal twins. Of particular interest were the differences in concordance rates for dry mouth, sinus infection and unusual sweating. The h2 for intraoral breath was 0.28 +/- 0.17 (NS), whereas the h2 for exhaled breath was 0.50 +/- 0.20 (p = .0207). The concordance rates of tongue coatings and malodor indicators were higher in identical twins than in fraternal twins. Intraoral breath VSC values were primarily attributable to environmental factors, whereas exhaled breath VSC values were partially explained by genetic factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335767PMC
http://dx.doi.org/10.1375/twin.14.6.568DOI Listing
December 2011

Naturally occurring variations in the human cholinesterase genes: heritability and association with cardiovascular and metabolic traits.

J Pharmacol Exp Ther 2011 Jul 14;338(1):125-33. Epub 2011 Apr 14.

Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California 92093-0657, USA.

Cholinergic neurotransmission in the central and autonomic nervous systems regulates immediate variations in and longer-term maintenance of cardiovascular function with acetylcholinesterase (AChE) activity that is critical to temporal responsiveness. Butyrylcholinesterase (BChE), largely confined to the liver and plasma, subserves metabolic functions. AChE and BChE are found in hematopoietic cells and plasma, enabling one to correlate enzyme levels in whole blood with hereditary traits in twins. Using both twin and unrelated subjects, we found certain single nucleotide polymorphisms (SNPs) in the ACHE gene correlated with catalytic properties and general cardiovascular functions. SNP discovery from ACHE resequencing identified 19 SNPs: 7 coding SNPs (cSNPs), of which 4 are nonsynonymous, and 12 SNPs in untranslated regions, of which 3 are in a conserved sequence of an upstream intron. Both AChE and BChE activity traits in blood were heritable: AChE at 48.8 ± 6.1% and BChE at 81.4 ± 2.8%. Allelic and haplotype variations in the ACHE and BCHE genes were associated with changes in blood AChE and BChE activities. AChE activity was associated with BP status and SBP, whereas BChE activity was associated with features of the metabolic syndrome (especially body weight and BMI). Gene products from cDNAs with nonsynonymous cSNPs were expressed and purified. Protein expression of ACHE nonsynonymous variant D134H (SNP6) is impaired: this variant shows compromised stability and altered rates of organophosphate inhibition and oxime-assisted reactivation. A substantial fraction of the D134H instability could be reversed in the D134H/R136Q mutant. Hence, common genetic variations at ACHE and BCHE loci were associated with changes in corresponding enzymatic activities in blood.
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http://dx.doi.org/10.1124/jpet.111.180091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126649PMC
July 2011
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