Heritable Contribution Research Articles

Incorporating functional annotation with bilevel continuous shrinkage for polygenic risk prediction

BackgroundGenetic variants can contribute differently to trait heritability by their functional categories, and recent studies have shown that incorporating functional annotation can improve the predictive performance of polygenic risk scores (PRSs). In addition, when only a small proportion of variants are causal variants, PRS methods that employ a Bayesian framework with shrinkage can account for such sparsity. It is possible that the annotation group level effect is also sparse. However, the number of PRS methods that incorporate both annotation information and shrinkage on effect sizes is limited. We propose a PRS method, PRSbils, which utilizes the functional annotation information with a bilevel continuous shrinkage prior to accommodate the varying genetic architectures both on the variant-specific level and on the functional annotation level.ResultsWe conducted simulation studies and investigated the predictive performance in settings with different genetic architectures. Results indicated that when there was a relatively large variability of group-wise heritability contribution, the gain in prediction performance from the proposed method was on average 8.0% higher AUC compared to the benchmark method PRS-CS. The proposed method also yielded higher predictive performance compared to PRS-CS in settings with different overlapping patterns of annotation groups and obtained on average 6.4% higher AUC. We applied PRSbils to binary and quantitative traits in three real world data sources (the UK Biobank, the Michigan Genomics Initiative (MGI), and the Korean Genome and Epidemiology Study (KoGES)), and two sources of annotations: ANNOVAR, and pathway information from the Kyoto Encyclopedia of Genes and Genomes (KEGG), and demonstrated that the proposed method holds the potential for improving predictive performance by incorporating functional annotations.ConclusionsBy utilizing a bilevel shrinkage framework, PRSbils enables the incorporation of both overlapping and non-overlapping annotations into PRS construction to improve the performance of genetic risk prediction. The software is available at https://github.com/styvon/PRSbils.

Cross-tissue patterns of DNA hypomethylation reveal genetically distinct histories of cell development

BackgroundEstablishment of DNA methylation (DNAme) patterns is essential for balanced multi-lineage cellular differentiation, but exactly how these patterns drive cellular phenotypes is unclear. While > 80% of CpG sites are stably methylated, tens of thousands of discrete CpG loci form hypomethylated regions (HMRs). Because they lack DNAme, HMRs are considered transcriptionally permissive, but not all HMRs actively regulate genes. Unlike promoter HMRs, a subset of non-coding HMRs is cell type-specific and enriched for tissue-specific gene regulatory functions. Our data further argues not only that HMR establishment is an important step in enforcing cell identity, but also that cross-cell type and spatial HMR patterns are functionally informative of gene regulation.ResultsTo understand the significance of non-coding HMRs, we systematically dissected HMR patterns across diverse human cell types and developmental timepoints, including embryonic, fetal, and adult tissues. Unsupervised clustering of 126,104 distinct HMRs revealed that levels of HMR specificity reflects a developmental hierarchy supported by enrichment of stage-specific transcription factors and gene ontologies. Using a pseudo-time course of development from embryonic stem cells to adult stem and mature hematopoietic cells, we find that most HMRs observed in differentiated cells (~ 60%) are established at early developmental stages and accumulate as development progresses. HMRs that arise during differentiation frequently (~ 35%) establish near existing HMRs (≤ 6 kb away), leading to the formation of HMR clusters associated with stronger enhancer activity. Using SNP-based partitioned heritability from GWAS summary statistics across diverse traits and clinical lab values, we discovered that genetic contribution to trait heritability is enriched within HMRs. Moreover, the contribution of heritability to cell-relevant traits increases with both increasing HMR specificity and HMR clustering, supporting the role of distinct HMR subsets in regulating normal cell function.ConclusionsOur results demonstrate that the entire HMR repertoire within a cell-type, rather than just the cell type-specific HMRs, stores information that is key to understanding and predicting cellular phenotypes. Ultimately, these data provide novel insights into how DNA hypo-methylation provides genetically distinct historical records of a cell’s journey through development, highlighting HMRs as functionally distinct from other epigenomic annotations.

Heritability of biting time behaviours in the major African malaria vector Anopheles arabiensis

BackgroundThe use of insecticide-treated nets for malaria control has been associated with shifts in mosquito vector feeding behaviour including earlier and outdoor biting on humans. The relative contribution of phenotypic plasticity and heritability to these behavioural shifts is unknown. Elucidation of the mechanisms behind these shifts is crucial for anticipating impacts on vector control.MethodsA novel portable semi-field system (PSFS) was used to experimentally measure heritability of biting time in the malaria vector Anopheles arabiensis in Tanzania. Wild An. arabiensis from hourly collections using the human landing catch (HLC) method were grouped into one of 3 categories based on their time of capture: early (18:00–21:00), mid (22:00–04:00), and late (05:00–07:00) biting, and placed in separate holding cages. Mosquitoes were then provided with a blood meal for egg production and formation of first filial generation (F1). The F1 generation of each biting time phenotype category was reared separately, and blood fed at the same time as their mothers were captured host-seeking. The resultant eggs were used to generate the F2 generation for use in heritability assays. Heritability was assessed by releasing F2 An. arabiensis into the PSFS, recording their biting time during a human landing catch and comparing it to that of their F0 grandmothers.ResultsIn PSFS assays, the biting time of F2 offspring (early: 18:00–21:00, mid: 22:00–04:00 or late: 05:00–07:00) was significantly positively associated with that of their wild-caught F0 grandmothers, corresponding to an estimated heritability of 0.110 (95% CI 0.003, 0.208). F2 from early-biting F0 were more likely to bite early than F2 from mid or late-biting F0. Similarly, the probability of biting late was higher in F2 derived from mid and late-biting F0 than from early-biting F0.ConclusionsDespite modest heritability, our results suggest that some of the variation in biting time is attributable to additive genetic variation. Selection can, therefore, act efficiently on mosquito biting times, highlighting the need for control methods that target early and outdoor biting mosquitoes.

Alpha-2-Macroglobulin (A2M) and Dopamine Receptor D2 (DRD2) expression analysis and Influence of Separation from Parents in Childhood on the Suicide and Self-injury Behavior and Psychological Adjustment in Adolescence.

To explore the influence of separation from parents in childhood on suicide and self-injury behavior and psychological adjustment in adolescence. A total of 880 subjects were selected, including 197 students who were separated from their parents in childhood and 683 students who were not separated from their parents in childhood. The scores of psychological resilience, self-compassion, forgiveness and suicide and self-injury were investigated and analyzed. Logistic regression analysis was made on the relationship between suicide and self-injury behavior and psychological adjustment in adolescence. The scores of psychological resilience, self-compassion, forgiveness and suicide and self-injury were statistically significant between children who were separated from their parents and those who were not separated. The students who were not separated had better psychological adjustment abilities and a lower rate of suicide and self-injury (P<0.05). There was a positive correlation between separation from parents in childhood and suicide and self-injury behavior and psychological adjustment in adolescence (P<0.05). The separation from parents in childhood is closely related to psychological resilience, forgiveness, self-compassion, and suicide-related psychological behavior and self-injury behavior in adolescence. Suicide and self-injury behavior can be reduced by reducing separation from parents in childhood and improving self-psychological adjustment ability in adolescence. During the past years, genetics, heritability, and genes' contribution to depression disorders have been well established. Alpha-2-Macroglobulin (A2M) and Dopamine Receptor D2 (DRD2) genes are very effective in behavioral and mood disorders. The results of this study showed the expression of these genes in different organs, especially in connection with the cerebrospinal system, so investigating the mechanism of their effect is very effective and promising, and it is hoped that they will be used in other research.

Comparative Analysis of Facial Coloration between Introduced and Source Populations of the Red Wood Ant Formica paralugubris.

The variation in the typical black-reddish color of red wood ants (Formica rufa group) has been recently suggested as a good indicator of habitat quality, being dependent on environmental conditions. However, the relative contribution of external factors and heritability in shaping this trait is poorly investigated. In this study, we compared the facial coloration of workers from four introduced populations of Formica paralugubris with those of the two Alpine populations from which they had been taken. We used a Relative Warp Analysis to describe the variations in the shape of this trait. We expected each introduced population to be more similar to its population of origin if the color pattern was predominantly genetically determined. On the contrary, due to the considerable differences in habitat type and climate between the Alps and the Apennines, we expected to observe differences between the introduced population and their origin population if the coloration was mostly environmentally determined. With one exception that we discuss, the results showed that ants from the two source populations had different phenotypes, and that the introduced populations had a shape similar to the population of origin, suggesting a stable genetic background. Surprisingly, the habitat type seems to have a less clear effect, even if within-population differences suggest the influence of very localized environmental factors. Finally, we found that the facial coloration shape is affected by the ant’s size, a result in line with previous studies.

Heritability and environmental influences on the onset of aortic valve sclerosis: a twin population study

Abstract Background Aortic valve sclerosis (AVSc) is the earliest manifestation of a life-threatening cardiovascular disorder, namely aortic valve stenosis (AS). AVSc is also recognized as a red flag linked to worse cardiovascular outcomes in high-risk coronary artery disease patients. However, the genetic background of AVSc is still unknown. Purpose To examine whether the heritability and environmental contributions play a role in the onset of AVSc using a sample of Italian twins. Methods The present study is based on the classical twin design. Twins, aged 50 to 70 years, already enrolled in the Italian Twin Register, were contacted and invited to undergo a clinical, echocardiographic, and complete carotid artery ultrasound examination at the our Center, between July 2017 and December 2021. The presence of AVSc was recognized as non-uniform thickening with or without spotty calcified areas of the aortic valve leaflets without a significant transvalvular gradient (maximum aortic velocity &amp;lt;2.5 m/s). Twin zygosity was assessed through a questionnaire on physical similarity during childhood, known to be ∼95% accurate. Tetrachoric twin correlations by zygosity were estimated with Mx Software using liability threshold saturated models and incorporating age as a covariate. Liability-threshold structural equation modelling was performed to decompose the phenotypic variance into contributions due to additive genetic (A), common environmental (C), and unique environmental (E) effects. Results A total of 216 adult twins (66 monozygotic, MZ and 42 dizygotic pairs, DZ; mean age 59.9±6.2) were enrolled in the study. The estimated prevalence rate of AVSc in the total sample was 29.2%. As significant sex differences were detected (males 45.2% and females 22.7%, p&amp;lt;0.01), the additional twin analyses were performed as intra-sex analyses. Females showed a greater tetrachoric correlation in MZ twins (r=0.37) compared to DZ twins (r=0.23), suggesting the existence of a genetic influence. Genetic factors, under the best (AE) model, accounted for 38% of the variance in liability to AVSc with the remaining contribution due to unique environmental influences (E = 62%). The contribution of the common environment (C) to the goodness of fit was negligible. The male group was too small for statistical calculation. Conclusion To our knowledge, the present study is the first to document the involvement of genetic factors in the development of AVSc. Our data also warrant further studies to both validate the findings obtained and to better explore the heritability of AVSc. Furthermore, our results provide a first evidence that an echocardiographic screening in individuals with relatives affected by AVSc has a scientific rational basis. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Italian Ministry of Health

The PRECEDE consortium: A longitudinal international cohort study of individuals with genetic risk or familial pancreatic cancer.

e16239 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with lack of effective early detection strategies. There is an incomplete understanding of who is at risk for PDAC development and the contribution of heritability to that risk. Further, efforts at biomarker development for detection of early stage disease have been hampered by small sample sizes, lack of coordination, and inadequate access to high quality clinical data and biospecimens in relevant clinical populations. The PRECEDE Consortium was established to serve as a collaborative international network of PDAC clinical and research centers to accelerate early detection advances by standardizing collection of clinical data and biospecimens from patients at increased risk for PDAC. The consortium goal is to increase the overall survival rate for PDAC to 50% in 10 years by enabling transformative biomarker-driven discoveries in early detection of high-risk premalignant lesions and early stage cancers. Methods: The PRECEDE Consortium (NCT04970056; precedestudy.org) launched in 2019 and began enrollment in May, 2020. Data and biospecimen sharing are required for centers to join the consortium, which is facilitated through use of standardized data and biospecimen collection, and a centralized database (PRECEDELink) managed by a data coordinating center (Arbor Research). Imaging and clinical sequencing data will be stored and analyzed via a PRECEDE solution in the Amazon Web Services cloud. Participants age 18-90 are enrolled into one of seven cohorts based on personal and/or family history of PDAC and carrier status of pathogenic germline variants (PGV) in cancer predisposition genes (CPG). Three-generation pedigrees are collected at enrolment from participants, and standardized clinical germline testing is offered. Blood sample collection for DNA, plasma, and serum is completed at enrollment, and repeated annually for individuals meeting guidelines for annual surveillance. Results: To date, 24 clinical sites have enrolled 2187 participants, with a target of 10,000 participants enrolled from100 sites over the next 5 years. Among enrolled patients, 55% meet criteria for annual surveillance by MRI or endoscopic ultrasound. Demographics of the cohort to date: 56% female; 73% white; 35% CPG PGV carriers; 32% meet criteria for familial pancreatic cancer. Conclusions: The PRECEDE Consortium study is a large international, longitudinal, prospective cohort study designed to accelerate the pace and scale of early diagnosis. Planned projects will address modifiers of risk, penetrance of disease, creating comprehensive risk models for clinical decision-making, and development and validation of biomarker assays. The PRECEDE Consortium provides a unique, innovative platform to bring together key stakeholders (academia, patients, public and private sector) to effect progress.

Measuring heritable contributions to Alzheimer's disease: polygenic risk score analysis with twins.

The heritability of Alzheimer’s disease estimated from twin studies is greater than the heritability derived from genome-based studies, for reasons that remain unclear. We apply both approaches to the same twin sample, considering both Alzheimer’s disease polygenic risk scores and heritability from twin models, to provide insight into the role of measured genetic variants and to quantify uncaptured genetic risk. A population-based heritability and polygenic association study of Alzheimer’s disease was conducted between 1986 and 2016 and is the first study to incorporate polygenic risk scores into biometrical twin models of Alzheimer’s disease. The sample included 1586 twins drawn from the Swedish Twin Registry which were nested within 1137 twin pairs (449 complete pairs and 688 incomplete pairs) with clinically based diagnoses and registry follow-up (Mage = 85.28, SD = 7.02; 44% male; 431 cases and 1155 controls). We report contributions of polygenic risk scores at P < 1 × 10−5, considering a full polygenic risk score (PRS), PRS without the APOE region (PRS.no.APOE) and PRS.no.APOE plus directly measured APOE alleles. Biometric twin models estimated the contribution of environmental influences and measured (PRS) and unmeasured genes to Alzheimer’s disease risk. The full PRS and PRS.no.APOE contributed 10.1 and 2.4% to Alzheimer’s disease risk, respectively. When APOE ɛ4 alleles were added to the model with the PRS.no.APOE, the total contribution was 11.4% to Alzheimer’s disease risk, where APOE ɛ4 explained 9.3% and PRS.no.APOE dropped from 2.4 to 2.1%. The total genetic contribution to Alzheimer’s disease risk, measured and unmeasured, was 71% while environmental influences unique to each twin accounted for 29% of the risk. The APOE region accounts for much of the measurable genetic contribution to Alzheimer’s disease, with a smaller contribution from other measured polygenic influences. Importantly, substantial background genetic influences remain to be understood.

Disentangling cortical functional connectivity strength and topography reveals divergent roles of genes and environment

The human brain varies across individuals in its morphology, function, and cognitive capacities. Variability is particularly high in phylogenetically modern regions associated with higher order cognitive abilities, but its relationship to the layout and strength of functional networks is poorly understood. In this study we disentangled the variability of two key aspects of functional connectivity: strength and topography. We then compared the genetic and environmental influences on these two features. Genetic contribution is heterogeneously distributed across the cortex and differs for strength and topography. In heteromodal areas genes predominantly affect the topography of networks, while their connectivity strength is shaped primarily by random environmental influence such as learning. We identified peak areas of genetic control of topography overlapping with parts of the processing stream from primary areas to network hubs in the default mode network, suggesting the coordination of spatial configurations across those processing pathways. These findings provide a detailed map of the diverse contribution of heritability and individual experience to the strength and topography of functional brain architecture.

Excess Heritability Contribution of Alcohol Consumption Variants in the "Missing Heritability" of Type 2 Diabetes Mellitus.

We aim to compare the relative heritability contributed by variants of behavior-related environmental phenotypes and elucidate the role of these factors in the conundrum of “missing heritability” of type 2 diabetes. Methods: We used Linkage-Disequilibrium Adjusted Kinships (LDAK) and LDAK-Thin models to calculate the relative heritability of each variant and compare the relative heritability for each phenotype. Biological analysis was carried out for the phenotype whose variants made a significant contribution. Potential hub genes were prioritized based on topological parameters of the protein-protein interaction network. We included 16 behavior-related phenotypes and 2607 valid variants. In the LDAK model, we found the variants of alcohol consumption and caffeine intake were identified as contributing higher relative heritability than that of the random variants. Compared with the relative expected heritability contributed by the variants associated with type 2 diabetes, the relative expected heritability contributed by the variants associated with these two phenotypes was higher. In the LDAK-Thin model, the relative heritability of variants of 11 phenotypes was statistically higher than random variants. Biological function analysis showed the same distributions among type 2 diabetes and alcohol consumption. We eventually screened out 31 hub genes interacting intensively, four of which were validated and showed the upregulated expression pattern in blood samples seen in type 2 diabetes cases. Conclusion: We found that alcohol consumption contributed higher relative heritability. Hub genes may influence the onset of type 2 diabetes by a mediating effect or a pleiotropic effect. Our results provide new insight to reveal the role of behavior-related factors in the conundrum of “missing heritability” of type 2 diabetes.

De novo germline mutation in the dual specificity phosphatase 10 gene accelerates autoimmune diabetes

Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.

Genome-wide association study of cardiac troponin I in the general population.

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes are unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study, and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization, we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.

GENETIC AND ENVIRONMENTAL CONTRIBUTIONS TO POSITIVE AFFECT: INSIGHTS FROM ADOLESCENT TWINS.

Disturbances in positive affect and reductions in social reward/interpersonal pleasure are common across a range of clinical disorders and are often related. We examined the relationship between the Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS-A), and other measures of positive affect in adolescents in a genetically informative research design. The sample consisted of 177 MZ and 136 same sex DZ twins drawn from a study of adolescent twins (M = 16.4 ± .97 years) who were part of the Wisconsin Twin Project. The self-report questionnaires included the Behavioral Activation Scale (BAS), Psychological Well-Being Scale, revised Early Adolescent Temperament Questionnaire (EATQR) and the adolescent version of the ACIPS (ACIPS-A). Structural equation modeling estimated the relative contribution of genetic and environmental factors to the phenotypic variance in each of the measures. Follow-up bivariate analyses parsed the genetic and environmental contributions to the phenotypic covariances between the ACIPS-A and each of the other measures of positive affect. We found evidence of moderate heritability for the ACIPS-A scale scores. Overall, models specifying additive genetic and unique environmental effects (AE models) were the most parsimonious models for each of the measures. Several of the measures showed moderate positive phenotypic intercorrelations, and all but one of these intercorrelations showed significant partial genetic underpinnings. Moreover, the bivariate biometric analyses indicated that the ACIPS-A also captures unique heritable variation. Thus, the ACIPS-A captures unique heritable contributions to social/interpersonal pleasure, as well as shared genetic variance with other measures of positive affectivity.

New insights into hallux valgus by whole exome sequencing study.

The traditional view is that the occurrence and development of hallux valgus (HV) are mainly due to environmental factors. Recent studies have suggested the large contribution of genetic heritability to HV, but it remains elusive about the genetic variants underlying the development of HV. To gain knowledge about the molecular mechanisms of HV pathogenesis by genetic approach, whole exome sequencing studies were performed in 10 individuals (7 affected by HV and 3 unaffected) from three independent families. Specific mutations were found to be related to the pathogenesis of HV and conform to the laws of inheritance. A total of 36 genes with functional candidate single nucleotide variants were identified. Genetic predisposition plays an important role in the development of HV. Interestingly, some of these genes are related to chronic arthritis, such as the complement encoding gene C7, or are related to long toe or long fingers, such as TTN, COL6A3, LARS, FIG4, and CBS. This study identified rare potentially pathogenic mutations represented by genes related to digital anomalies and chronic arthritis underlying the familial types of HV, which acquired new insights into the genetic and physiological foundations of HV, thereby might improve accurate prevention and drug development for HV.

Quantifying the contribution of dominance deviation effects to complex trait variation in biobank-scale data

SummaryThe proportion of variation in complex traits that can be attributed to non-additive genetic effects has been a topic of intense debate. The availability of biobank-scale datasets of genotype and trait data from unrelated individuals opens up the possibility of obtaining precise estimates of the contribution of non-additive genetic effects. We present an efficient method to estimate the variation in a complex trait that can be attributed to additive (additive heritability) and dominance deviation (dominance heritability) effects across all genotyped SNPs in a large collection of unrelated individuals. Over a wide range of genetic architectures, our method yields unbiased estimates of additive and dominance heritability. We applied our method, in turn, to array genotypes as well as imputed genotypes (at common SNPs with minor allele frequency [MAF] > 1%) and 50 quantitative traits measured in 291,273 unrelated white British individuals in the UK Biobank. Averaged across these 50 traits, we find that additive heritability on array SNPs is 21.86% while dominance heritability is 0.13% (about 0.48% of the additive heritability) with qualitatively similar results for imputed genotypes. We find no statistically significant evidence for dominance heritability ( accounting for the number of traits tested) and estimate that dominance heritability is unlikely to exceed 1% for the traits analyzed. Our analyses indicate a limited contribution of dominance heritability to complex trait variation.

1036 Familial aggregation of stillbirth

Stillbirth occurs in 1 out of every 168 pregnancies and accounts for 60% of perinatal deaths in the U.S. Prior studies assessed mother-daughter inherited predisposition to stillbirth and miscarriage but found little to no evidence of risk transmission. We conducted a retrospective cohort study to determine the familial aggregation and high-risk extended pedigrees of stillbirth. We utilized the Utah Population Database (UPDB), a population-based genealogy linked with state fetal death record database to identify mothers who suffered stillbirth between 1978 and 2018. The pedigrees of related family members were determined to identify the first-degree (father, mother and full-siblings), second-degree (grandparents, aunts/uncles, and nieces/nephews) and third-degree (first cousins) relatives of the affected mothers (probands). High-risk pedigrees with excess clustering of stillbirth were identified using the Familial Standardized Incidence Ratio (FSIR), which compares the incidence of stillbirth in a family to its expected incidence in the UPDB population. Mothers with stillbirth (N=7756) and their first-, second-, and third-degree relatives (n=391,797) were identified (Table 1 and Table 2). High-risk pedigrees (n=197) with excess clustering of stillbirth (FSIR ≥ 2; P-value < 0.05; Observed stillbirths ≥ 10) were identified for mothers (probands; n=1764 [22.7%]). Table 1 shows the top 10 high-risk pedigrees with statistically significant evidence for familial aggregation of stillbirth. Stillbirth persisted among 2nd degree relatives (0.34%) and 3rd degree relatives (0.38%) (Table 2). Familial aggregation of stillbirth occurs and is present in 22.7% of women with stillbirth. Stillbirth persisted in more distant relatives, which may further support a heritable or genetic contribution, as environmental exposures in distant relatives are expected to be randomly distributed compared with a proband’s exposures. Future studies should examine genetic variants in these high-risk families to identify de novo and inherited genes associated with stillbirth.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Accessibility to Parks and Trails and Physical Health Measures in CATSLife: Evaluating Selection

Associations of obesity and cardiovascular health with neighborhood walkability have been observed in the literature; however, limited research has evaluated self-selection that may underlie associations. We measured accessibility to parks and trails using geospatial measurements as well as self-reported activity-friendliness of neighborhoods (ease of walking, biking, and recreating) in 1140 participants (ages 28-49 years) in the ongoing Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife). Physical health indicators included BMI, resting heart rate, and mean arterial blood pressure. The relative similarity of siblings’ accessibility was evaluated to consider self-selection; all models were adjusted for sociodemographics including education. BMI was associated with accessibility to parks, with each increasing log(mile) distance associated with 1.2 BMI unit increase (se=.49, p<0.02). Self-reported neighborhood activity-friendliness was comparable in prediction of BMI (p<0.01). Greater trail accessibility was associated with lower resting heart rate (b=-.30, se=.14, p<0.04) and mean arterial pressure (b=-0.33, se=0.14, p<0.03), whereas self-reported neighborhood activity-friendliness was not associated (p>0.40). Measures of park accessibility tended to be more similar among identical twins (median ICC = 0.30) than fraternal twins or siblings (median ICC = 0.15) or siblings in adoptive families (median ICC = 0.12), excluding siblings who live together. Measures of trail accessibility were consistent across sibling types (median ICCs = 0.25-0.27). Sibling similarity for park accessibility modestly increased with genetic relatedness suggesting potential heritable contributions, whereas comparable similarity was apparent for trail accessibility. Altogether, small associations were observed for park and trail access with physical health, with indications of environmental selection.

Germline variants are associated with increased primary melanoma tumor thickness at diagnosis.

Germline genetic variants have been identified, which predispose individuals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness.To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness.The analyses utilized 10 604 individuals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated individuals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 individuals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry.We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P < 5 × 10−8) with tumor thickness. Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.

Association of Family History With Incidence and Outcomes of Aortic Dissection

BackgroundAortic dissection (AD) is a life-threatening emergency. However, the heritability and association of family history with late outcomes are unclear. ObjectivesThe purpose of this study was to evaluate the effect of family history of AD on the incidence and prognosis of AD and estimate the heritability and environmental contribution in AD in Taiwan. MethodsBoth cross-sectional and cohort studies were conducted using Taiwan National Health Insurance database. A registry parent–offspring relationship algorithm was used to reconstruct the genealogy of this population for heritability estimation. The cross-sectional study included 23,868 patients with a diagnosis of AD in 2015. The prevalence and adjusted relative risks (RRs) were evaluated, and the liability threshold model was used to examine the effects of heritability and environmental factors. Furthermore, a 1:10 propensity score–matched cohort comprising AD patients with or without a family history of AD was included to compare late outcomes in the cohort study. ResultsA family history of AD in first-degree relatives was associated with an RR of 6.82 (95% confidence interval [CI]: 5.12 to 9.07). The heritability of AD was estimated to be 57.0% for genetic factors, and 3.1% and 40.0% for shared and nonshared environmental factors, respectively. After excluding individuals with Marfan syndrome or bicuspid aortic valve, a family history of AD was associated with an RR of 6.56 (95% CI: 4.92 to 8.77) for AD. Furthermore, patients with AD and a family history of AD had a higher risk of later aortic surgery than those with AD without a family history (subdistribution hazard ratio: 1.40; 95% CI: 1.12 to 1.76). ConclusionsA family history of AD was a strong risk factor for AD. Furthermore, patients with AD with a family history of AD had a higher risk of later aortic surgery than those with no family history of AD.

Abstract C050: Deleterious coding variants in African American Hereditary Prostate Cancer Study (AAHPC) families

Abstract Purpose: Prostate cancer is the most common cancer in males, with a ~1.5-2-fold higher incidence in African American men when compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ~33% of the familial risk. A portion of the undefined risk may be due to rare susceptibility variants. The African American Hereditary Prostate Cancer (AAHPC) Study, established in 1997, enrolled 77 African American families from seven clinical sites across the United States. The aim of this study is to identify rare, predictive, deleterious variants through exome sequencing of 99 cases from families selected from the AAHPC families and three 1000 Genome controls. Methods: To explore the contribution of rare variation in coding regions to prostate cancer risk, we sequenced the exomes of 99 AAHPC cases at a mean coverage of 30x. Post-variant calling quality control (QC) was implemented using Golden Helix SVS 8 software with filters set for removal of variants with Read Depth &amp;gt;10, Quality Score &amp;gt;10, and Quality Score: Read Depth Ratio &amp;gt; 0.5. Mendelian inconsistency was checked using PLINK. Prioritization of all candidate genes/variants was evaluated using online databases 1000 Genome and bioinformatics tool ANNOVAR for non-reference allele frequency and predictions of functional impact. Conclusions: Through exome sequencing of 99 AAHPC cases and three 1000 Genome controls, we identified 37 nonsynonymous single-nucleotide variants that are considered damaging by at least one predictive scoring tool in our candidate genes. Interesting candidate variants were found in known cancer susceptibility loci BRCA2, MSR1, PCNT, STAT3, WRN and ZFHX3. Future results are pending additional QC and analyses to determine which variants are shared by related individuals within each family compared to those not seen in the controls. Citation Format: Deyana D. Lewis, Shukmei Wong, Angela S. Baker, Joan E. Bailey-Wilson, John D. Carpten, Cheryl D. Cropp. Deleterious coding variants in African American Hereditary Prostate Cancer Study (AAHPC) families [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C050.