The Polygenic and Monogenic Basis of Blood Traits and Diseases

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation. Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive as

Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment

Previous research has shown that genes play a substantial role in determining a person's susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden

Analysis of shared heritability in common disorders of the brain

Paroxysmal Cerebral Disorder

Prevalence of mild cognitive impairment is higher in men: The Mayo Clinic Study of Aging(CME)

Objective: We investigated the prevalence of mild cognitive impairment (MCI) in Olmsted County, MN, using in-person evaluations and published criteria. Methods: We evaluated an age-and sex-stratified random sample of Olmsted County residents who were 70-89 years old on October 1, 2004, using the Clinical Dementia Rating Scale, a neurologic evaluation, and neuropsychological testing to assess 4 cognitive domains: memory, executive function, language, and visuospatial skills. Information for each participant was reviewed by an adjudication panel and a diagnosis of normal cognition, MCI, or dementia was made using published criteria. Results: Among 1,969 subjects without dementia, 329 subjects had MCI, with a prevalence of 16.0% (95% confidence interval [CI] 14.4-17.5) for any MCI, 11.1% (95% CI 9.8-12.3) for amnestic MCI, and 4.9% (95% CI 4.0-5.8) for nonamnestic MCI. The prevalence of MCI increased with age and was higher in men. The prevalence odds ratio (OR) in men was 1.54 (95% CI 1.21-1.96; adjusted for age, education, and nonparticipation). The prevalence was also higher in subjects who never married and in subjects with an APOE ε3ε4 or ε4ε4 genotype. MCI prevalence decreased with increasing number of years of education (p for linear trend \u3c0.0001). Conclusions: Our study suggests that approximately 16% of elderly subjects free of dementia are affected by MCI, and amnestic MCI is the most common type. The higher prevalence of MCI in men may suggest that women transition from normal cognition directly to dementia at a later age but more abruptly. © 2010 by AAN Enterprises, Inc

Reaching the “Hard-to-Reach” Sexual and Gender Diverse Communities for Population-Based Research in Cancer Prevention and Control: Methods for Online Survey Data Collection and Management

Purpose: Around 5% of United States (U.S.) population identifies as Sexual and Gender Diverse (SGD), yet there is limited research around cancer prevention among these populations. We present multi-pronged, low-cost, and systematic recruitment strategies used to reach SGD communities in New Mexico (NM), a state that is both largely rural and racially/ethnically classified as a “majority-minority” state. Methods: Our recruitment focused on using: (1) Every Door Direct Mail (EDDM) program, by the United States Postal Services (USPS); (2) Google and Facebook advertisements; (3) Organizational outreach via emails to publicly available SGD-friendly business contacts; (4) Personal outreach via flyers at clinical and community settings across NM. Guided by previous research, we provide detailed descriptions on using strategies to check for fraudulent and suspicious online responses, that ensure data integrity. Results: A total of 27,369 flyers were distributed through the EDDM program and 436,177 impressions were made through the Google and Facebook ads. We received a total of 6,920 responses on the eligibility survey. For the 5,037 eligible respondents, we received 3,120 (61.9%) complete responses. Of these, 13% (406/3120) were fraudulent/suspicious based on research-informed criteria and were removed. Final analysis included 2,534 respondents, of which the majority (59.9%) reported hearing about the study from social media. Of the respondents, 49.5% were between 31-40 years, 39.5% were Black, Hispanic, or American Indian/Alaskan Native, and 45.9% had an annual household income below $50,000. Over half (55.3%) were assigned male, 40.4% were assigned female, and 4.3% were assigned intersex at birth. Transgender respondents made up 10.6% (n=267) of the respondents. In terms of sexual orientation, 54.1% (n=1371) reported being gay or lesbian, 30% (n=749) bisexual, and 15.8% (n=401) queer. A total of 756 (29.8%) respondents reported receiving a cancer diagnosis and among screen-eligible respondents, 66.2% reported ever having a Pap, 78.6% reported ever having a mammogram, and 84.1% reported ever having a colonoscopy. Over half of eligible respondents (58.7%) reported receiving Human Papillomavirus vaccinations. Conclusion: Study findings showcase effective strategies to reach communities, maximize data quality, and prevent the misrepresentation of data critical to improve health in SGD communities. Copyright © 2022 Myers, Jaffe, Kanda, Pankratz, Tawfik, Wu, McClain, Mishra, Kano, Madhivanan and Adsul.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]