Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the ...need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (<ext-link ext-link-type="uri" xlink:href="http://www.mrbase.org">http://www.mrbase.org</ext-link>): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.
The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma ...protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.
Genome-wide association studies of psychiatric disorders have been criticized for their lack of explaining a considerable proportion of the heritability established in twin and family studies. ...Genome-wide association studies of major depressive disorder in particular have so far been unsuccessful in detecting genome-wide significant single nucleotide polymorphisms (SNPs). Using two recently proposed methods designed to estimate the heritability of a phenotype that is attributable to genome-wide SNPs, we show that SNPs on current platforms contain substantial information concerning the additive genetic variance of major depressive disorder. To assess the consistency of these two methods, we analyzed four other complex phenotypes from different domains. The pattern of results is consistent with estimates of heritability obtained in twin studies carried out in the same population.
Abstract
Genomic imprinting is an epigenetic mechanism leading to parent-of-origin silencing of alleles. So far, the precise number of imprinted regions in humans is uncertain. In this study, we ...leveraged genome-wide DNA methylation in whole blood measured longitudinally at three time points (birth, childhood and adolescence) and genome-wide association studies (GWAS) data in 740 mother-child duos from the Avon Longitudinal Study of parents and children to identify candidate imprinted loci. We reasoned that cis-meQTLs at genomic regions that were imprinted would show strong evidence of parent-of-origin associations with DNA methylation, enabling the detection of imprinted regions. Using this approach, we identified genome-wide significant cis-meQTLs that exhibited parent-of-origin effects (POEs) at 82 loci, 34 novel and 48 regions previously implicated in imprinting (3.7−10<P < 10−300). Using an independent dataset from the Brisbane Systems Genetic Study, we replicated 76 out of the 82 identified loci. POEs were remarkably consistent across time points and were so strong at some loci that methylation levels enabled good discrimination of parental transmissions at these and surrounding genomic regions. The implication is that parental allelic transmissions could be modelled at many imprinted (and linked) loci in GWAS of unrelated individuals given a combination of genetic and methylation data. Novel regions showing parent of origin effects on methylation will require replication using a different technology and further functional experiments to confirm that such effects arise through a genomic imprinting mechanism.
ABSTRACT
Phenotypic heterogeneity of depression has been cited as one of the causes of the limited success to detect genetic variants in genome‐wide studies. The 7‐item Hospital Anxiety and ...Depression Scale (HADS‐D) was developed to detect depression in individuals with physical health problems. An initial psychometric analysis showed that a short version (“HADS‐4”) is less heterogeneous and hence more reliable than the full scale, and correlates equally strong with a DSM‐oriented depression scale. We compared the HADS‐D and the HADS‐4 to assess the benefits of using less heterogeneous phenotype measures in genetic analyses. We compared HADS‐D and HADS‐4 in three separate analyses: (1) twin‐ and family‐based heritability estimation, (2) SNP‐based heritability estimation using the software GCTA, and (3) a genome‐wide association study (GWAS). The twin study resulted in heritability estimates between 18% and 25%, with additive genetic variance being the largest component. There was also evidence for assortative mating and a dominance component of genetic variance, with HADS‐4 having slightly lower estimates of assortment. Importantly, when estimating heritability from SNPs, the HADS‐D did not show a significant genetic variance component, while for the HADS‐4, a statistically significant amount of heritability was estimated. Moreover, the HADS‐4 had substantially more SNPs with small P‐values in the GWAS analysis than did the HADS‐D. Our results underline the benefits of using more homogeneous phenotypes in psychiatric genetic analyses. Homogeneity can be increased by focusing on core symptoms of disorders, thus reducing the noise in aggregate phenotypes caused by substantially different symptom profiles.
This study reports on the main criteria used by Canadian cardiac surgery residency program committees (RPCs) to select applicants and the perceptions of Canadian medical students interested in ...cardiac surgery.
A 50-question online survey was sent to all 12 Canadian cardiac surgery RPCs. A similar 52-question online survey targeted at Canadian medical students interested in applying to cardiac surgery residency programs was distributed. Data from both surveys were analyzed using descriptive statistics.
A total of 62% of all cardiac surgery RPC members (66 of 106) participated, including committee members from all 12 programs (range: 1-12 members per program; 9%-100% response rate per program) and 67% of program directors (8 of 12). Forty-one Canadian medical students (22 pre-clerks 54%, 2 MD/PhD students 5%, and 17 clinical clerks 41%) participated. Committee members considered the following criteria to be most important when selecting candidates: on-service clinical performance, the interview, quality of reference letters from cardiac surgeons, and completing a rotation at the target program’s institution. In contrast, the following criteria relating to the candidate were considered to be less important: wanting to practice in the city or province of training, having a connection to the program location, and personally knowing committee members. Medical students’ perceptions were concordant regarding what factors are the most important but they overestimated the influence of non-clinical factors and research productivity in increasing their competitiveness.
Canadian cardiac surgery residency programs seek applicants who demonstrate clinical excellence, as assessed by surgical rotations and reference letters from colleagues, and strong interview performance.
Cette étude fait état des principaux critères utilisés par les comités des programmes de résidence (CPR) canadiens en chirurgie cardiaque pour sélectionner les candidats, ainsi que des perceptions des étudiants en médecine canadiens qui s’intéressent à la chirurgie cardiaque.
Un sondage en ligne comptant 50 questions a été envoyé aux 12 CPR canadiens en chirurgie cardiaque. Un sondage en ligne semblable (comptant 52 questions) a été distribué aux étudiants en médecine qui souhaitaient soumettre leur candidature à un programme de résidence en chirurgie cardiaque au Canada. Les données des deux sondages ont été analysées à l’aide de statistiques descriptives.
Au total, 62 % des membres de CPR en chirurgie cardiaque (66 sur 106) ont répondu au sondage, y compris des membres des comités des 12 programmes (plage : 1 à 12 membres par programme; taux de réponse de 9 à 100 % par programme) et 67 % des directeurs de programme (8 sur 12). Au total, 41 étudiants en médecine canadiens (22 en préexternat 54 %, 2 étudiants au M.D./Ph. D. 5 % et 17 stagiaires en formation clinique 41 %) ont répondu au sondage. Les membres du comité ont considéré les critères suivants comme étant les plus importants dans le choix de candidats : le rendement clinique en service, l’entrevue, la qualité des lettres de recommandation de chirurgiens cardiaques et la réalisation d’un stage dans l’établissement associé au programme. En revanche, les critères suivants étaient considérés comme moins importants : le désir de pratiquer dans la ville ou la province de formation, un lien avec le lieu du programme, et la connaissance personnelle de membres du co-mité. Les perceptions des étudiants en médecine concordaient quant aux facteurs les plus importants, mais les étudiants surestimaient l’influence de facteurs non cliniques et de la productivité en recherche dans l’aspect concurrentiel de leur candidature.
Les programmes de résidence canadiens en chirurgie cardiaque recherchent des candidats forts d’une excellence clinique, évaluée par les stages en chirurgie et les lettres de recommandation de collègues, et offrant une bonne performance en entrevue.
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Studies suggest that fish consumption can restrict weight gain. However, little is known about how fish consumption affects gestational weight gain (GWG), and whether this relationship depends on ...genetic makeup.
To examine the association between fish consumption and GWG, and whether this relationship is dependent on molecular genetic predisposition to obesity.
A nested case-cohort study based on the Danish National Birth Cohort (DNBC) sampling the most obese women (n = 990) and a random sample of the remaining participants (n = 1,128). Replication of statistically significant findings was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 4,841). We included 32 body mass index (BMI) associated single nucleotide polymorphisms (SNPs) and 5 SNPs found associated with GWG. BMI associated SNPs were combined in a genetic risk score (GRS). Associations between consumption of fish, GRS or individual variants and GWG were analysed, and interactions between fish and the GRS or individual variants were examined.
In the DNBC, each portion/week (150 g) of fatty fish was associated with a higher GWG of 0.58 kg (95% CI: 0.16, 0.99, P<0.01). For total fish and lean fish, similar patterns were observed, but these associations were not statistically significant. We found no association between GRS and GWG, and no interactions between GRS and dietary fish on GWG. However, we found an interaction between the PPARG Pro12Ala variant and dietary fish. Each additional Pro12Ala G-allele was associated with a GWG of -0.83 kg (95% CI: -1.29, -0.37, P<0.01) per portion/week of dietary fish, with the same pattern for both lean and fatty fish. In ALSPAC, we were unable to replicate these findings.
We found no consistent evidence of association between fish consumption and GWG, and our results indicate that the association between dietary fish and GWG has little or no dependency on GRS or individual SNPs.
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