Sex-Specific Parental Effects on Offspring Lipid Levels

Background: Plasma lipid levels are highly heritable traits, but known genetic loci can only explain a small portion of their heritability. Methods and Results: In this study, we analyzed the role of parental levels of total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), and triglycerides (TGs) in explaining the values of the corresponding traits in adult offspring. We also evaluated the contribution of nongenetic factors that influence lipid traits (age, body mass index, smoking, medications, and menopause) alone and in combination with variability at the genetic loci known to associate with TC, LDL‐C, HDL‐C, and TG levels. We performed comparisons among different sex‐specific regression models in 416 families from the Framingham Heart Study and 304 from the SardiNIA cohort. Models including parental lipid levels explain significantly more of the trait variation than models without these measures, explaining up to ≈39% of the total trait variation. Of this variation, the parent‐of‐origin effect explains as much as ≈15% and it does so in a sex‐specific way. This observation is not owing to shared environment, given that spouse‐pair correlations were negligible (\u3c1.5% explained variation in all cases) and is distinct from previous genetic and acquired factors that are known to influence serum lipid levels. Conclusions: These findings support the concept that unknown genetic and epigenetic contributors are responsible for most of the heritable component of the plasma lipid phenotype, and that, at present, the clinical utility of knowing age‐matched parental lipid levels in assessing risk of dyslipidemia supersedes individual locus effects. Our results support the clinical utility of knowing parental lipid levels in assessing future risk of dyslipidemia

Diverse Convergent Evidence in the Genetic Analysis of Complex Disease: Coordinating Omic, Informatic, and Experimental Evidence to Better Identify and Validate Risk Factors

In omic research, such as genome wide association studies, researchers seek to repeat their results in other datasets to reduce false positive findings and thus provide evidence for the existence of true associations. Unfortunately this standard validation approach cannot completely eliminate false positive conclusions, and it can also mask many true associations that might otherwise advance our understanding of pathology. These issues beg the question: How can we increase the amount of knowledge gained from high throughput genetic data? To address this challenge, we present an approach that complements standard statistical validation methods by drawing attention to both potential false negative and false positive conclusions, as well as providing broad information for directing future research. The Diverse Convergent Evidence approach (DiCE) we propose integrates information from multiple sources (omics, informatics, and laboratory experiments) to estimate the strength of the available corroborating evidence supporting a given association. This process is designed to yield an evidence metric that has utility when etiologic heterogeneity, variable risk factor frequencies, and a variety of observational data imperfections might lead to false conclusions. We provide proof of principle examples in which DiCE identified strong evidence for associations that have established biological importance, when standard validation methods alone did not provide support. If used as an adjunct to standard validation methods this approach can leverage multiple distinct data types to improve genetic risk factor discovery/validation, promote effective science communication, and guide future research directions

Complex Patterns of Association between Pleiotropy and Transcription Factor Evolution

Pleiotropy hasbeen claimedtoconstraingeneevolution but specificmechanisms andextent of these constraintshavebeen difficult to demonstrate. The expansion of molecular data makes it possible to investigate these pleiotropic effects. Few classes of genes have been characterized as intensely as human transcription factors ( TFs). We therefore analyzed the evolutionary rates of full TF proteins, along with theirDNAbinding domains and protein-protein interacting domains ( PID) in light of the degree of pleiotropy, measured by the number of TF-TF interactions, or the number of DNA-binding targets. Data were extracted fromthe ENCODE Chip-Seq dataset, the String v 9.2 database, and the NHGRIGWAScatalog. Evolutionary rates of proteins and domainswere calculated using the PAML CodeML package. Our analysis shows that the numbers of TF-TF interactions and DNA binding targets associated with constrained gene evolution; however, the constraint caused by the number of DNA binding targets was restricted to the DNA binding domains, whereas the number of TF-TF interactions constrained the full protein and did so more strongly. Additionally, we found a positive correlation between the number of protein-PIDs and the evolutionary rates of the protein-PIDs. These findings show that not only does pleiotropy associate with constrained protein evolution but the constraint differs by domain function. Finally, we show that GWASassociated TF genes are more highly pleiotropic. TheGWASdata illustrates thatmutations inhighly pleiotropic genes aremore likely to be associated with disease phenotypes

Patterns of risk for diabetic retinopathy in the Mumbai slums: The Aditya Jyot Diabetic Retinopathy in Urban Mumbai Slums Study (AJ-DRUMSS) Report 3.

Diabetes onset precedes diabetic retinopathy (DR) by 5-10 years, but many people with diabetes remain free of this microvascular complication. Our aim was to identify risk factors for DR progression in a unique and diverse population, the slums of Mumbai. We performed a nested case-control study of 1163 diabetics over 40 years of age from slums in 18 wards of Mumbai. Data was collected on 33 variables and assessed for association with DR using both univariate and multivariate analyses. Stratified analyses were also performed on males and females, separately. Among hypertensive individuals we also assessed whether duration of hypertension associated with DR. Of 31 non-correlated variables analysed as risk factors for DR, 15 showed evidence of significant association. The most prominent included sex, where being a female associated with decreased odds of DR, while longer duration of diabetes and poor glycaemic control associated with increased odds. The duration of diabetes effect was partially, but significantly, mediated by age of diabetes diagnoses (8.6% of variance explained, p = 0.012). Obesity as measured by several measures, including body mass index (BMI) and measures of central obesity had a negative association with DR; increased measures of obesity consistently reduced odds of DR. As in most earlier studies, DR was associated with the duration of diabetes and glycaemic control. However, other factors, especially obesity related measures were associated with DR, in ways that contrast with most prior studies. These results indicated that the overall pattern of association in the Mumbai slums was novel. Thus, in previously uncharacterized populations, such as the slums that we examined, it is important to evaluate all risk factors de novo to appropriately assess patterns of association as the patterns of association with DR can be complex and population specific

Patterns of risk for diabetic retinopathy in the Mumbai slums: The Aditya Jyot Diabetic Retinopathy in Urban Mumbai Slums Study (AJ-DRUMSS) Report 3

Diabetes onset precedes diabetic retinopathy (DR) by 5–10 years, but many people with diabetes remain free of this microvascular complication. Our aim was to identify risk factors for DR progression in a unique and diverse population, the slums of Mumbai. We performed a nested case-control study of 1163 diabetics over 40 years of age from slums in 18 wards of Mumbai. Data was collected on 33 variables and assessed for association with DR using both univariate and multivariate analyses. Stratified analyses were also performed on males and females, separately. Among hypertensive individuals we also assessed whether duration of hypertension associated with DR. Of 31 non-correlated variables analysed as risk factors for DR, 15 showed evidence of significant association. The most prominent included sex, where being a female associated with decreased odds of DR, while longer duration of diabetes and poor glycaemic control associated with increased odds. The duration of diabetes effect was partially, but significantly, mediated by age of diabetes diagnoses (8.6% of variance explained, p = 0.012). Obesity as measured by several measures, including body mass index (BMI) and measures of central obesity had a negative association with DR; increased measures of obesity consistently reduced odds of DR. As in most earlier studies, DR was associated with the duration of diabetes and glycaemic control. However, other factors, especially obesity related measures were associated with DR, in ways that contrast with most prior studies. These results indicated that the overall pattern of association in the Mumbai slums was novel. Thus, in previously uncharacterized populations, such as the slums that we examined, it is important to evaluate all risk factors de novo to appropriately assess patterns of association as the patterns of association with DR can be complex and population specific

Hypertension only–Stepwise multivariate regression.

Hypertension only–Stepwise multivariate regression.</p

All results for univariate and multivariate analyses.

All results for univariate and multivariate analyses.</p

Sex stratified analyses of DR association–univariate analyses.

Sex stratified analyses of DR association–univariate analyses.</p

S8 Table -

Diabetes onset precedes diabetic retinopathy (DR) by 5–10 years, but many people with diabetes remain free of this microvascular complication. Our aim was to identify risk factors for DR progression in a unique and diverse population, the slums of Mumbai. We performed a nested case-control study of 1163 diabetics over 40 years of age from slums in 18 wards of Mumbai. Data was collected on 33 variables and assessed for association with DR using both univariate and multivariate analyses. Stratified analyses were also performed on males and females, separately. Among hypertensive individuals we also assessed whether duration of hypertension associated with DR. Of 31 non-correlated variables analysed as risk factors for DR, 15 showed evidence of significant association. The most prominent included sex, where being a female associated with decreased odds of DR, while longer duration of diabetes and poor glycaemic control associated with increased odds. The duration of diabetes effect was partially, but significantly, mediated by age of diabetes diagnoses (8.6% of variance explained, p = 0.012). Obesity as measured by several measures, including body mass index (BMI) and measures of central obesity had a negative association with DR; increased measures of obesity consistently reduced odds of DR. As in most earlier studies, DR was associated with the duration of diabetes and glycaemic control. However, other factors, especially obesity related measures were associated with DR, in ways that contrast with most prior studies. These results indicated that the overall pattern of association in the Mumbai slums was novel. Thus, in previously uncharacterized populations, such as the slums that we examined, it is important to evaluate all risk factors de novo to appropriately assess patterns of association as the patterns of association with DR can be complex and population specific.</div