Publications by authors named "Sarah C Nelson"

34 Publications

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation.

Blood Adv 2020 07;4(14):3224-3233

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.

Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.
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http://dx.doi.org/10.1182/bloodadvances.2020001927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391140PMC
July 2020

Who's on third? Regulation of third-party genetic interpretation services.

Genet Med 2020 01 12;22(1):4-11. Epub 2019 Aug 12.

Baylor College of Medicine, Center for Medical Ethics and Health Policy, Houston, TX, USA.

In recent years, third-party genetic interpretation services have emerged to help individuals understand their raw genetic data obtained from researchers, clinicians, and direct-to-consumer genetic testing companies. The objectives of these services vary but include matching users to genetic relatives, selling customized diet and fitness plans, and providing health risk assessments. As these services proliferate, concerns are being raised about their accuracy, safety, and privacy practices. Thus far, US regulatory agencies have not taken an official position with respect to third-party genetic interpretation services, which has caused uncertainty regarding whether and how they might be regulated. To clarify this area, we analyzed their potential oversight by four US agencies that generally have been active in the regulation of genetic testing services and information: the Centers for Medicare and Medicaid Services, the Food and Drug Administration, the Department of Health and Human Services' Office of Civil Rights, and the Federal Trade Commission. We conclude that the scope of federal jurisdiction over third-party genetic interpretation services-while limited-could be appropriate at this time, subject to agency clarification and appropriate exercise of oversight.
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http://dx.doi.org/10.1038/s41436-019-0627-6DOI Listing
January 2020

Genetic analyses of diverse populations improves discovery for complex traits.

Nature 2019 06 19;570(7762):514-518. Epub 2019 Jun 19.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.
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http://dx.doi.org/10.1038/s41586-019-1310-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785182PMC
June 2019

Third-Party Genetic Interpretation Tools: A Mixed-Methods Study of Consumer Motivation and Behavior.

Am J Hum Genet 2019 07 13;105(1):122-131. Epub 2019 Jun 13.

Department of Bioethics and Humanities, University of Washington School of Medicine, Seattle, WA 98195, USA.

In an effort to meet ethical obligations and/or participant expectations, researchers may consider offering "raw" or uninterpreted genetic data for result return. It is therefore important to understand the motivations, behaviors, and perspectives of individuals who might choose to access raw data before such return becomes routine. In the direct-to-consumer (DTC) context, where raw data are often made available to customers, the use of third-party interpretation tools has raised concerns about genotype accuracy, data privacy, reliability of interpretation, and consumption of limited health care resources. However, relatively little is known about why individuals access raw data or what they do with the information received from third-party interpretation. Accordingly, we conducted a survey on raw data access and third-party tool usage among 1,137 DTC customers recruited through social media. Most survey respondents (89%) reported downloading their raw data. Among downloaders, 94% used at least one tool, most commonly Promethease (63%) or GEDmatch (84%). More than half (56%) used both health-related and non-health-related tools and differed significantly from those who used only one tool type in terms of demographics, participation in research, DTC tests ordered, and testing motivations. Exploratory interviews were conducted with 10 respondents and illustrated how social networking, initial lack of interesting findings, and general curiosity contributed to use of multiple tool types. These results suggest that even when initially motivated by ancestry and genealogy, consumers frequently also pursue health information in a largely unregulated and expanding suite of third-party tools, raising both challenges and opportunities for the professional genetics community.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612532PMC
July 2019

A content analysis of the views of genetics professionals on race, ancestry, and genetics.

AJOB Empir Bioeth 2018 Oct-Dec;9(4):222-234. Epub 2019 Jan 4.

b Department of Pediatrics , University of Washington.

Over the past decade, the proliferation of genetic studies on human health and disease has reinvigorated debates about the appropriate role of race and ancestry in research and clinical care. Here we report on the responses of genetics professionals to a survey about their views on race, genetics, and ancestry across the domains of science, medicine, and society. Through a qualitative content analysis of free-text comments from 515 survey respondents, we identified key themes pertaining to multiple meanings of race, the use of race as a proxy for genetic ancestry, and the relevance of race and ancestry to health. Our findings suggest that for many genetics professionals the questions of what race is and what race means remain both professionally and personally contentious. Looking ahead as genomics is translated into the practice of precision medicine and as learning health care systems offer continued improvements in care through integrated research, we argue for nuanced considerations of both race and genetic ancestry across research and care settings.
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http://dx.doi.org/10.1080/23294515.2018.1544177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516754PMC
November 2019

Discovery of common and rare genetic risk variants for colorectal cancer.

Nat Genet 2019 01 3;51(1):76-87. Epub 2018 Dec 3.

Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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http://dx.doi.org/10.1038/s41588-018-0286-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358437PMC
January 2019

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.

Pain 2019 Mar;160(3):579-591

Center for Pain Research and Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.
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http://dx.doi.org/10.1097/j.pain.0000000000001438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377338PMC
March 2019

Pathways to ethnic-racial identity development and psychological adjustment: The differential associations of cultural socialization by parents and peers.

Dev Psychol 2018 Nov 27;54(11):2166-2180. Epub 2018 Sep 27.

Department of Psychology.

Ethnic-racial identity (ERI) development is a central developmental process for youth of color. Although a great deal of research establishes the importance of cultural socialization by parents to the development of ERI, limited empirical work has examined peers' role in these processes. This study uses 4 cross-sectional data sets ( = 127, 312, 257, and 238, mean age = 17.96-18.24) followed by a meta-analytic summary to test a path model of ERI development and parent and peer cultural socialization and their associations with psychological adjustment in a diverse sample of emerging adults. The final sample size adjusted meta-analytic model indicated that parent ethnic socialization predicted both ERI exploration and commitment while only peer preparation for bias predicted ERI commitment. In turn, ERI commitment and exploration predicted more positive mental health. The findings of this study highlight the importance of both parents and peers to cultural socialization processes during emerging adulthood. In particular, this study suggests that the messages peers impart about prejudice play a unique role in the development of ERI. The findings have important implications about the unique role peers play in communicating messages about prejudice as well as for ERI and the psychological adjustment of youth of color at this developmental stage. Additionally, these cross-sectional findings provide a preliminary but robust model from which researchers can frame future longitudinal work in this area. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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http://dx.doi.org/10.1037/dev0000597DOI Listing
November 2018

Can I take my normal painkillers doctor? Therapeutic management of pain following dermatological procedures.

Australas J Dermatol 2019 Feb 5;60(1):19-22. Epub 2018 Sep 5.

Dermatologic Surgery Unit, Skin Cancer Institute, Tauranga, Bay of Plenty, New Zealand.

Dermatological procedures performed purely under local anaesthesia can provide excellent intraoperative analgesia. However, post-procedure patients can have significant pain. Consequences of pain include patient distress, poor compliance with dressings and subsequent delayed wound healing as well as the potential fear and avoidance of further procedures. Anecdotally the same postoperative analgesia regime is given to all dermatology patients. There is a general fear by dermatologists of nonsteroidal anti-inflammatory drugs (NSAIDs) due to perceived risk of postoperative bleeding and of tramadol due to its sedative effects. Understanding of pharmacology within the patient population and their comorbidities is necessary in choosing the appropriate analgesic regime. We reviewed the most commonly used analgesics, giving a summary of the important pharmacology and evidence of their use in the literature in order to allow clinicians to give individual approach to managing post-procedure analgesia.
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http://dx.doi.org/10.1111/ajd.12892DOI Listing
February 2019

Ethnic-racial typicality and its relation to ethnic identity and psychological functioning.

Cultur Divers Ethnic Minor Psychol 2018 07 24;24(3):400-413. Epub 2018 May 24.

Department of Psychology, University of Minnesota, Twin Cities.

Objectives: Ethnic identity development is considered a central task of adolescence and emerging adulthood for ethnic minority individuals. Although the process of developing a coherent ethnic identity has received attention from researchers, there has been little work done to elucidate the content of ethnic identity. This study uses an inductive mixed-methods approach to address 1 aspect of ethnic identity content: typicality, or the degree of perceived similarity individuals feel to their ethnic-racial group.

Method: Participants included 974 college students at 3 universities-66% women, average age 20.4 years, 5% Black, 30% Asian, 10% Latinx, 40% White, 11% Multiracial, 1% American Indian, and 4% Other race-ethnicity. Thematic analysis was used to code qualitative categories on what makes individuals typical of and atypical of their ethnic group. Codes were used to quantitatively assess relations between aspects of typicality, ethnic identity, and mental health.

Results: Findings suggest that individuals judged their typicality and atypicality to their ethnic group by focusing on skin color, hair, facial features; values related to family, achievement, and religion-spirituality; and behaviors related to arts-media, sports, spending time with others, and food. Additionally, findings demonstrated that most individuals feel typical of their ethnic group and, of importance, that level of perceived typicality was inversely related to measures of ethnic identity and well-being. Finally, participants differed in their feeling of being typical by ethnic-racial group identifications.

Conclusions: Ethnic-racial typicality provides valuable information about ethnic identity content and is related to important mental health outcomes. (PsycINFO Database Record
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http://dx.doi.org/10.1037/cdp0000193DOI Listing
July 2018

Identity and the body: Trajectories of body esteem from adolescence to emerging adulthood.

Dev Psychol 2018 06 5;54(6):1159-1171. Epub 2018 Apr 5.

Department of Psychology, University of Minnesota-Twin Cities.

Although Erikson (1968) originally conceptualized identity development as a process of becoming at home in one's body, little work has been done linking identity development and research on the body. This study examines how trajectories of the development of body esteem over time are related to young people's sense of identity and psychological functioning in a longitudinal sample from age 10 to 24 (N = 967). Using group-based trajectory modeling, three cubic subgroups were determined for each of the three types of body esteem: appearance, weight, and attribution. These groups demonstrated significant variations in the ways in which body esteem changes over time. These trajectory groups importantly differed in relationship to gender, identity coherence, identity confusion, and psychological functioning. Results are discussed in terms of the need to use a sociocultural perspective to explore the body's relation to identity development and the importance of disaggregating mean-level findings using person-centered approaches to determine high-risk groups. (PsycINFO Database Record
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http://dx.doi.org/10.1037/dev0000435DOI Listing
June 2018

Genetic variants in sex hormone pathways and the risk of type 2 diabetes among African American, Hispanic American, and European American postmenopausal women in the US.

J Diabetes 2018 Jun 6;10(6):524-533. Epub 2018 Apr 6.

Department of Epidemiology, Brown University, Providence, Rhode Island, USA.

Background: Sex hormones are implicated in the development of diabetes. However, whether genetic variations in sex hormone pathways (SHPs) contribute to the risk of type 2 diabetes mellitus (T2DM) remains to be determined. This study investigated associations between genetic variations in all candidate genes in SHPs and T2DM risk among a cohort of women participating in the Women's Health Initiative (WHI).

Methods: Single nucleotide polymorphisms (SNPs) located within 30 kb upstream and downstream of SHP genes were comprehensively examined in 8180 African American, 3498 Hispanic American, and 3147 European American women in the WHI. In addition, whether significant SNPs would be replicated in independent populations was examined.

Results: After adjusting for age, region, and ancestry estimates and correcting for multiple testing, seven SNPs were significantly associated with the risk of T2DM among Hispanic American women were identified in the progesterone receptor (PGR) gene, with rs948516 showing the greatest significance (odds ratio 0.67; 95% confidence interval 0.57-0.78; P = 8.8 × 10 ; false discovery rate, Q = 7.8 × 10 ). These findings were not replicated in other ethnic groups in the WHI or in sex-combined analyses in replication studies.

Conclusion: Significant signals were identified implicating the PGR gene in T2DM development in Hispanic American women in the WHI, which are consistent with genome-wide association studies findings linking PGR to glucose homeostasis. Nevertheless, the PGR SNPs-T2DM association was not statistically significant in other ethnic populations. Further studies, especially sex-specific analyses, are needed to confirm the findings and clarify the role of SHPs in T2DM.
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http://dx.doi.org/10.1111/1753-0407.12648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980699PMC
June 2018

"Bridge to the Literature"? Third-Party Genetic Interpretation Tools and the Views of Tool Developers.

J Genet Couns 2018 08 7;27(4):770-781. Epub 2018 Feb 7.

Department of Bioethics & Humanities, University of Washington, Seattle, WA, USA.

Patients and health care consumers can obtain access to their "raw," or uninterpreted, genetic data from direct-to-consumer genetic testing companies, researchers, or providers and pursue self-directed analysis via third-party interpretation tools. Yet relatively little is known about the nature of currently available interpretation tools or the motivations of tool developers. We conducted a structured content analysis of 23 third-party interpretation tool websites and supporting information, tracking features such as types of information returned, modes of generating and presenting that information, and privacy and security measures. We additionally conducted qualitative interviews with a subset of 10 tool developers. A majority of tools (16 of 23, or 70%) offer some type of health or wellness-related information, often extracted from publicly available variant annotation databases. Half of those interviewed characterized their activities as "bridging" users to the scientific literature rather than interpretation, for which they gave a variety of scientific, ethical, and regulatory justifications. The scale, heterogeneity, and complexity of information available from third-party interpretation are unprecedented. While developers aim to enlighten and empower tool users, interpretation-free "bridging" to rapidly evolving databases may instead impose burdens on genetic counselors and other health care providers asked to provide further contextualization and explanation.
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http://dx.doi.org/10.1007/s10897-018-0217-9DOI Listing
August 2018

Genome-wide minor histocompatibility matching as related to the risk of graft-versus-host disease.

Blood 2017 02 21;129(6):791-798. Epub 2016 Nov 21.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA.

The risk of acute graft-versus-host disease (GVHD) is higher after allogeneic hematopoietic cell transplantation (HCT) from unrelated donors as compared with related donors. This difference has been explained by increased recipient mismatching for major histocompatibility antigens or minor histocompatibility antigens. In the current study, we used genome-wide arrays to enumerate single nucleotide polymorphisms (SNPs) that produce graft-versus-host (GVH) amino acid coding differences between recipients and donors. We then tested the hypothesis that higher degrees of genome-wide recipient GVH mismatching correlate with higher risks of GVHD after allogeneic HCT. In HLA-genotypically matched sibling recipients, the average recipient mismatching of coding SNPs was 9.35%. Each 1% increase in genome-wide recipient mismatching was associated with an estimated 20% increase in the hazard of grades III-IV GVHD (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.05-1.37; = .007) and an estimated 22% increase in the hazard of stage 2-4 acute gut GVHD (HR, 1.22; 95% CI, 1.02-1.45; = .03). In HLA-A, B, C, DRB1, DQA1, DQB1, DPA1, DPB1-phenotypically matched unrelated recipients, the average recipient mismatching of coding SNPs was 17.3%. The estimated risks of GVHD-related outcomes in HLA-phenotypically matched unrelated recipients were low, relative to the large difference in genome-wide mismatching between the 2 groups. In contrast, the risks of GVHD-related outcomes were higher in HLA-DP GVH-mismatched unrelated recipients than in HLA-matched sibling recipients. Taken together, these results suggest that the increased GVHD risk after unrelated HCT is predominantly an effect of HLA-mismatching.
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http://dx.doi.org/10.1182/blood-2016-09-737700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301826PMC
February 2017

Improved imputation accuracy in Hispanic/Latino populations with larger and more diverse reference panels: applications in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Hum Mol Genet 2016 08 26;25(15):3245-3254. Epub 2016 Jun 26.

Department of Biostatistics, University of Washington, Seattle, WA, USA.

Imputation is commonly used in genome-wide association studies to expand the set of genetic variants available for analysis. Larger and more diverse reference panels, such as the final Phase 3 of the 1000 Genomes Project, hold promise for improving imputation accuracy in genetically diverse populations such as Hispanics/Latinos in the USA. Here, we sought to empirically evaluate imputation accuracy when imputing to a 1000 Genomes Phase 3 versus a Phase 1 reference, using participants from the Hispanic Community Health Study/Study of Latinos. Our assessments included calculating the correlation between imputed and observed allelic dosage in a subset of samples genotyped on a supplemental array. We observed that the Phase 3 reference yielded higher accuracy at rare variants, but that the two reference panels were comparable at common variants. At a sample level, the Phase 3 reference improved imputation accuracy in Hispanic/Latino samples from the Caribbean more than for Mainland samples, which we attribute primarily to the additional reference panel samples available in Phase 3. We conclude that a 1000 Genomes Project Phase 3 reference panel can yield improved imputation accuracy compared with Phase 1, particularly for rare variants and for samples of certain genetic ancestry compositions. Our findings can inform imputation design for other genome-wide association studies of participants with diverse ancestries, especially as larger and more diverse reference panels continue to become available.
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http://dx.doi.org/10.1093/hmg/ddw174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179925PMC
August 2016

Use of metaphors about exome and whole genome sequencing.

Am J Med Genet A 2016 May 29;170A(5):1127-33. Epub 2016 Jan 29.

Department of Pediatrics, University of Washington, Seattle, Washington.

Clinical and research uses of exome and whole genome sequencing (ES/WGS) are growing rapidly. An enhanced understanding of how individuals conceptualize and communicate about sequencing results is needed to ensure effective, mutual exchange of information between care providers and patients and between researchers and participants. Focus groups and interviews participants were recruited to discuss their attitudes and preferences for receiving hypothetical results from ES/WGS. African Americans were intentionally oversampled. We qualitatively analyzed participants' speech to identify unsolicited metaphorical language pertaining to genes and health, and grouped these occurrences into metaphorical concepts. Participants compared genetic information to physical objects including tools, weapons, contents of boxes, and formal documents or reports. These metaphorical concepts centered on several key themes, including locus of control; containment versus release of information; and desirability, usability, interpretability, and ownership of genetic results. Metaphorical language is often used intentionally or unintentionally in discussions about receiving results from ES/WGS in both clinical and research settings. Awareness of the use of metaphorical language and attention to its varied meanings facilitates effective communication about return of ES/WGS results. In turn, both should foster shared and informed decision-making and improve the translation of genetic information by clinicians and researchers.
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http://dx.doi.org/10.1002/ajmg.a.37571DOI Listing
May 2016

Genome-wide Association Study of Platelet Count Identifies Ancestry-Specific Loci in Hispanic/Latino Americans.

Am J Hum Genet 2016 Feb 21;98(2):229-42. Epub 2016 Jan 21.

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Platelets play an essential role in hemostasis and thrombosis. We performed a genome-wide association study of platelet count in 12,491 participants of the Hispanic Community Health Study/Study of Latinos by using a mixed-model method that accounts for admixture and family relationships. We discovered and replicated associations with five genes (ACTN1, ETV7, GABBR1-MOG, MEF2C, and ZBTB9-BAK1). Our strongest association was with Amerindian-specific variant rs117672662 (p value = 1.16 × 10(-28)) in ACTN1, a gene implicated in congenital macrothrombocytopenia. rs117672662 exhibited allelic differences in transcriptional activity and protein binding in hematopoietic cells. Our results underscore the value of diverse populations to extend insights into the allelic architecture of complex traits.
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http://dx.doi.org/10.1016/j.ajhg.2015.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746331PMC
February 2016

Genetic Diversity and Association Studies in US Hispanic/Latino Populations: Applications in the Hispanic Community Health Study/Study of Latinos.

Am J Hum Genet 2016 Jan;98(1):165-84

Division of Cardiovascular Sciences, NHLBI, NIH, Bethesda, MD 20892, USA.

US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population-structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy-Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rican, Mexican, and Central and South American). To control for variation among groups, we developed a multi-dimensional clustering method to define a "genetic-analysis group" variable that retains many properties of self-identified background while achieving substantially greater genetic homogeneity within groups and including participants with non-specific self-identification. In GWASs of 22 biomedical traits, we used a linear mixed model (LMM) including pairwise empirical KCs to account for familial relatedness, PCs for ancestry, and genetic-analysis groups for additional group-associated effects. Including the genetic-analysis group as a covariate accounted for significant trait variation in 8 of 22 traits, even after we fit 20 PCs. Additionally, genetic-analysis groups had significant heterogeneity of residual variance for 20 of 22 traits, and modeling this heteroscedasticity within the LMM reduced genomic inflation for 19 traits. Furthermore, fitting an LMM that utilized a genetic-analysis group rather than a self-identified background group achieved higher power to detect previously reported associations. We expect that the methods applied here will be useful in other studies with multiple ethnic groups, admixture, and relatedness.
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http://dx.doi.org/10.1016/j.ajhg.2015.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716704PMC
January 2016

Transitions in young adulthood: Exploring trajectories of parent-child conflict during college.

J Couns Psychol 2015 Jul 18;62(3):545-51. Epub 2015 May 18.

Department of Psychology.

This longitudinal study examined trajectories of parent-child conflict from the perspective of young adults during their college years. Using group-based trajectory modeling, self-report data from 3 time points were analyzed and 4 conflict trajectories emerged. The largest group of students (65%) had low, stable levels of parent-child conflict. Ten percent of the sample reported increases in parent-child conflict, and the remainder (25%) reported 1 of 2 patterns of decreasing parent-child conflict. Students with at least 1 immigrant parent were more likely to experience changes in parent-child conflict in contrast to peers with no immigrant parents. Contrary to our hypotheses, individuals in the groups in which conflict was decreasing were more likely to experience psychological distress. Results are discussed in terms of implications for the heterogeneity of conflict trajectories over time, particularly considering the contextual influence of immigrant family status.
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http://dx.doi.org/10.1037/cou0000078DOI Listing
July 2015

Characterization of large structural genetic mosaicism in human autosomes.

Am J Hum Genet 2015 Mar;96(3):487-97

Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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http://dx.doi.org/10.1016/j.ajhg.2015.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375431PMC
March 2015

Acquired chromosomal anomalies in chronic lymphocytic leukemia patients compared with more than 50,000 quasi-normal participants.

Cancer Genet 2014 Jan-Feb;207(1-2):19-30. Epub 2014 Jan 17.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Pretherapy patients with chronic lymphocytic leukemia (CLL) from US Intergroup trial E2997 were analyzed with single nucleotide polymorphism microarrays to detect acquired chromosomal anomalies. The four CLL-typical anomalies (11q-, +12, 13q-, and 17p-) were found at expected frequencies. Acquired anomalies in other regions account for 70% of the total detected anomalies, and their number per participant has a significant effect on progression-free survival after adjusting for the effects of 17p- (and other covariates). These results were compared with those from a previous study of more than 50,000 participants from the GENEVA consortium of genome-wide association studies, which analyzed individuals with a variety of medical conditions and healthy controls. The percentage of individuals with acquired anomalies is vastly different between the two studies (GENEVA 0.8%; E2997 80%). The composition of the anomalies also differs, with GENEVA having a higher percentage of acquired uniparental disomies and a lower percentage of deletions. The four common CLL anomalies are among the most frequent in GENEVA participants, some of whom may have CLL-precursor conditions or early stages of CLL. However, the patients from E2997 (and other studies of symptomatic CLL) have recurrent acquired anomalies that were not found in GENEVA participants, thus identifying genomic changes that may be unique to symptomatic stages of CLL.
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http://dx.doi.org/10.1016/j.cancergen.2014.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074414PMC
May 2014

How much do soldiers know about the morphine they carry on operations? A questionnaire study of knowledge and understanding of the morphine auto-injector on Op HERRICK 17.

J R Army Med Corps 2015 Mar 23;161(1):27-31. Epub 2014 Feb 23.

General Duties Medical Officer, 3 Medical Regiment, Catterick, UK.

Introduction: Morphine auto-injectors are issued to all British soldiers on operations in Afghanistan who deploy forward of Camp Bastion, the main British base. Previous studies have reviewed the effectiveness of various pre-hospital analgesics, but there is no record of the knowledge and confidence of the relatively medically untrained soldiers who carry and use intramuscular morphine on the battlefield. The aim of this study was to assess soldiers' knowledge and confidence of the morphine auto-injector with a view to guiding further training.

Methods: Structured questionnaire distributed to soldiers in two patrol bases in Helmand Province during Op HERRICK 17.

Results: 232 questionnaires were completed by a range of ranks and trades. 100% had received mandatory training on the auto-injector and over 70% had received more advanced training. Confidence in using the auto-injector was high, with 47% rating their confidence level as 10/10. Overall, factual knowledge was good with the mean score for the questionnaire being 7.9/10; 95% of respondents knew how to document the use of morphine and 79% knew when a second dose could safely be administered. Some misunderstanding of contraindications was revealed: 9% of answers were incorrect, and 47% wrongly answered that administering morphine to a patient changes the triage category.

Conclusions: The majority of soldiers received far more than the minimum required training on the use of the morphine auto-injector. Confidence in using the device is high and generally knowledge is good. The authors suggest that deployed medical personnel in forward locations maintain regular training to soldiers on the morphine auto-injector in order to ensure that casualties receive analgesia appropriately and promptly.
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http://dx.doi.org/10.1136/jramc-2013-000203DOI Listing
March 2015

Imputation-based genomic coverage assessments of current human genotyping arrays.

G3 (Bethesda) 2013 Oct 3;3(10):1795-807. Epub 2013 Oct 3.

Department of Biostatistics, University of Washington, Seattle, Washington, 98195.

Microarray single-nucleotide polymorphism genotyping, combined with imputation of untyped variants, has been widely adopted as an efficient means to interrogate variation across the human genome. "Genomic coverage" is the total proportion of genomic variation captured by an array, either by direct observation or through an indirect means such as linkage disequilibrium or imputation. We have performed imputation-based genomic coverage assessments of eight current genotyping arrays that assay from ~0.3 to ~5 million variants. Coverage was determined separately in each of the four continental ancestry groups in the 1000 Genomes Project phase 1 release. We used the subset of 1000 Genomes variants present on each array to impute the remaining variants and assessed coverage based on correlation between imputed and observed allelic dosages. More than 75% of common variants (minor allele frequency > 0.05) are covered by all arrays in all groups except for African ancestry, and up to ~90% in all ancestries for the highest density arrays. In contrast, less than 40% of less common variants (0.01 < minor allele frequency < 0.05) are covered by low density arrays in all ancestries and 50-80% in high density arrays, depending on ancestry. We also calculated genome-wide power to detect variant-trait association in a case-control design, across varying sample sizes, effect sizes, and minor allele frequency ranges, and compare these array-based power estimates with a hypothetical array that would type all variants in 1000 Genomes. These imputation-based genomic coverage and power analyses are intended as a practical guide to researchers planning genetic studies.
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http://dx.doi.org/10.1534/g3.113.007161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789804PMC
October 2013

Non-organic hearing loss.

Authors:
Sarah C Nelson

J R Army Med Corps 2012 Dec;158(4):329-30

5th Regiment Royal Artillery, Catterick.

Annual hearing tests are compulsory in the British Armed Forces. This case report presents a 24-year old soldier who was found to have severe deterioration on her annual audiogram without any significant noise exposure. After two years of specialist audiological investigations she was diagnosed with non-organic hearing loss; further interrogation of her social circumstances suggested potential psychosocial triggers. This diagnosis should be considered early in military primary care in those with objective hearing loss on audiogram where there has been no exposure to significant noise.
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http://dx.doi.org/10.1136/jramc-158-04-11DOI Listing
December 2012

Genome-wide association scan of dental caries in the permanent dentition.

BMC Oral Health 2012 Dec 21;12:57. Epub 2012 Dec 21.

Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA.

Unlabelled:

Background: Over 90% of adults aged 20 years or older with permanent teeth have suffered from dental caries leading to pain, infection, or even tooth loss. Although caries prevalence has decreased over the past decade, there are still about 23% of dentate adults who have untreated carious lesions in the US. Dental caries is a complex disorder affected by both individual susceptibility and environmental factors. Approximately 35-55% of caries phenotypic variation in the permanent dentition is attributable to genes, though few specific caries genes have been identified. Therefore, we conducted the first genome-wide association study (GWAS) to identify genes affecting susceptibility to caries in adults.

Methods: Five independent cohorts were included in this study, totaling more than 7000 participants. For each participant, dental caries was assessed and genetic markers (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Due to the heterogeneity among the five cohorts regarding age, genotyping platform, quality of dental caries assessment, and study design, we first conducted genome-wide association (GWA) analyses on each of the five independent cohorts separately. We then performed three meta-analyses to combine results for: (i) the comparatively younger, Appalachian cohorts (N = 1483) with well-assessed caries phenotype, (ii) the comparatively older, non-Appalachian cohorts (N = 5960) with inferior caries phenotypes, and (iii) all five cohorts (N = 7443). Top ranking genetic loci within and across meta-analyses were scrutinized for biologically plausible roles on caries.

Results: Different sets of genes were nominated across the three meta-analyses, especially between the younger and older age cohorts. In general, we identified several suggestive loci (P-value ≤ 10E-05) within or near genes with plausible biological roles for dental caries, including RPS6KA2 and PTK2B, involved in p38-depenedent MAPK signaling, and RHOU and FZD1, involved in the Wnt signaling cascade. Both of these pathways have been implicated in dental caries. ADMTS3 and ISL1 are involved in tooth development, and TLR2 is involved in immune response to oral pathogens.

Conclusions: As the first GWAS for dental caries in adults, this study nominated several novel caries genes for future study, which may lead to better understanding of cariogenesis, and ultimately, to improved disease predictions, prevention, and/or treatment.
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http://dx.doi.org/10.1186/1472-6831-12-57DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574042PMC
December 2012

GWASTools: an R/Bioconductor package for quality control and analysis of genome-wide association studies.

Bioinformatics 2012 Dec 10;28(24):3329-31. Epub 2012 Oct 10.

Department of Biostatistics, University of Washington, Seattle, WA, USA.

GWASTools is an R/Bioconductor package for quality control and analysis of genome-wide association studies (GWAS). GWASTools brings the interactive capability and extensive statistical libraries of R to GWAS. Data are stored in NetCDF format to accommodate extremely large datasets that cannot fit within R's memory limits. The documentation includes instructions for converting data from multiple formats, including variants called from sequencing. GWASTools provides a convenient interface for linking genotypes and intensity data with sample and single nucleotide polymorphism annotation.
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http://dx.doi.org/10.1093/bioinformatics/bts610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519456PMC
December 2012

Detectable clonal mosaicism from birth to old age and its relationship to cancer.

Nat Genet 2012 May 6;44(6):642-50. Epub 2012 May 6.

Department of Biostatistics, University of Washington, Seattle, Washington, USA.

We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5-10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2-3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6-18).
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http://dx.doi.org/10.1038/ng.2271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366033PMC
May 2012
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