Replication in genetic studies of complex traits

2004 ◽  
Vol 68 (6) ◽  
pp. 646-657 ◽  
Author(s):  
Mikko J. Sillanpää ◽  
Kari Auranen
Keyword(s):  
Complex Traits ◽  
Genetic Studies

scholarly journals Shared associations identify causal relationships between gene expression and immune cell phenotypes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Christiane Gasperi ◽  
Sung Chun ◽  
Shamil R. Sunyaev ◽  
Chris Cotsapas
Keyword(s):  
Complex Traits ◽  
Direct Evidence ◽  
Immune Cell ◽  
Genetic Locus ◽  
Causal Variant ◽  
Causal Relationships ◽  
Genetic Studies ◽  
Two Factors ◽  
Gene Regulatory ◽  
Cell Phenotypes

AbstractGenetic mapping studies have identified thousands of associations between common variants and hundreds of human traits. Translating these associations into mechanisms is complicated by two factors: they fall into gene regulatory regions; and they are rarely mapped to one causal variant. One way around these limitations is to find groups of traits that share associations, using this genetic link to infer a biological connection. Here, we assess how many trait associations in the same locus are due to the same genetic variant, and thus shared; and if these shared associations are due to causal relationships between traits. We find that only a subset of traits share associations, with many due to causal relationships rather than pleiotropy. We therefore suggest that simply observing overlapping associations at a genetic locus is insufficient to infer causality; direct evidence of shared associations is required to support mechanistic hypotheses in genetic studies of complex traits.

scholarly journals The limits of normal approximation for adult height

2021 ◽  
Author(s):  
Sergei A. Slavskii ◽  
Ivan A. Kuznetsov ◽  
Tatiana I. Shashkova ◽  
Georgii A. Bazykin ◽  
Tatiana I. Axenovich ◽  
...  
Keyword(s):  
Complex Traits ◽  
Adult Height ◽  
Normal Approximation ◽  
Classical Model ◽  
Model Complexity ◽  
Test Case ◽  
Genetic Studies ◽  
Quantitative Genetic ◽  
Profound Influence ◽  
Log Normal

AbstractAdult height inspired the first biometrical and quantitative genetic studies and is a test-case trait for understanding heritability. The studies of height led to formulation of the classical polygenic model, that has a profound influence on the way we view and analyse complex traits. An essential part of the classical model is an assumption of additivity of effects and normality of the distribution of the residuals. However, it may be expected that the normal approximation will become insufficient in bigger studies. Here, we demonstrate that when the height of hundreds of thousands of individuals is analysed, the model complexity needs to be increased to include non-additive interactions between sex, environment and genes. Alternatively, the use of log-normal approximation allowed us to still use the additive effects model. These findings are important for future genetic and methodologic studies that make use of adult height as an exemplar trait.

scholarly journals PAWE-3D: visualizing power for association with error in case-control genetic studies of complex traits

2005 ◽  
Vol 21 (20) ◽  
pp. 3935-3937 ◽  
Author(s):  
D. Gordon ◽  
C. Haynes ◽  
J. Blumenfeld ◽  
S. J. Finch
Keyword(s):  
Complex Traits ◽  
Case Control ◽  
Genetic Studies

scholarly journals Shared associations identify causal relationships between gene expression and immune cell phenotypes

2020 ◽  
Author(s):  
Christiane Gasperi ◽  
Sung Chun ◽  
Shamil R. Sunyaev ◽  
Chris Cotsapas
Keyword(s):  
Complex Traits ◽  
Direct Evidence ◽  
Immune Cell ◽  
Genetic Locus ◽  
Causal Variant ◽  
Causal Relationships ◽  
Genetic Studies ◽  
Two Factors ◽  
Gene Regulatory ◽  
Cell Phenotypes

AbstractGenetic mapping studies have identified thousands of associations between common variants and hundreds of human traits. Translating these associations into mechanisms is complicated by two factors: they fall into gene regulatory regions; and they are rarely mapped to one causal variant. One way around these limitations is to find groups of traits that share associations, using this genetic link to infer a biological connection. Here, we assess how many trait associations in the same locus are due to the same genetic variant, and thus shared; and if these shared associations are due to causal relationships between traits. We find that only a subset of traits share associations, with most due to causal relationships rather than pleiotropy. We therefore suggest that simply observing overlapping associations at a genetic locus is insufficient to infer causality; direct evidence of shared associations is required to support mechanistic hypotheses in genetic studies of complex traits.

scholarly journals Genome-wide methylation data improves dissection of the effect of smoking on body mass index

PLoS Genetics ◽  
2021 ◽  
Vol 17 (9) ◽  
pp. e1009750
Author(s):  
Carmen Amador ◽  
Yanni Zeng ◽  
Michael Barber ◽  
Rosie M. Walker ◽  
Archie Campbell ◽  
...  
Keyword(s):  
Complex Traits ◽  
Genetic Basis ◽  
Environmental Changes ◽  
Total Contribution ◽  
Genetic Studies ◽  
Socioeconomic Changes ◽  
Genome Wide ◽  
A Genome ◽  
Causes Of Disease ◽  
Wide Perspective

Variation in obesity-related traits has a genetic basis with heritabilities between 40 and 70%. While the global obesity pandemic is usually associated with environmental changes related to lifestyle and socioeconomic changes, most genetic studies do not include all relevant environmental covariates, so the genetic contribution to variation in obesity-related traits cannot be accurately assessed. Some studies have described interactions between a few individual genes linked to obesity and environmental variables but there is no agreement on their total contribution to differences between individuals. Here we compared self-reported smoking data and a methylation-based proxy to explore the effect of smoking and genome-by-smoking interactions on obesity related traits from a genome-wide perspective to estimate the amount of variance they explain. Our results indicate that exploiting omic measures can improve models for complex traits such as obesity and can be used as a substitute for, or jointly with, environmental records to better understand causes of disease.

scholarly journals The Critical Needs and Challenges for Genetic Architecture Studies in Africa

2018 ◽  
Author(s):  
Alicia R. Martin ◽  
Solomon Teferra ◽  
Marlo Möller ◽  
Eileen G. Hoal ◽  
Mark J. Daly
Keyword(s):  
Genetic Diversity ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Prediction Models ◽  
Research Capacity ◽  
Genetic Associations ◽  
Genetic Studies ◽  
Environmental Pressures ◽  
Homogeneous Population ◽  
Genetic Risk Prediction

Human genetic studies have long been vastly Eurocentric, raising a key question about the generalizability of these study findings to other populations. Because humans originated in Africa, these populations retain more genetic diversity, and yet individuals of African descent have been tremendously underrepresented in genetic studies. The diversity in Africa affords ample opportunities to improve fine-mapping resolution for associated loci, discover novel genetic associations with phenotypes, build more generalizable genetic risk prediction models, and better understand the genetic architecture of complex traits and diseases subject to varying environmental pressures. Thus, it is both ethically and scientifically imperative that geneticists globally surmount challenges that have limited progress in African genetic studies to date while meaningfully including African investigators, as greater inclusivity and enhanced research capacity affords enormous opportunities to accelerate genomic discoveries that translate more effectively to all populations. We review the advantages and challenges of studying the genetic architecture of complex traits and diseases in Africa. For example, with greater genetic diversity comes greater ancestral heterogeneity; this higher level of understudied diversity can yield novel genetic findings, but some methods that assume homogeneous population structure and work well in European populations may work less well in the presence of greater diversity and heterogeneity in African populations. Consequently, we advocate for methodological development that will accelerate studies important for all populations, especially those currently underrepresented in genetics.

GIST: A web tool for collecting gene information

1999 ◽  
Vol 1 (2) ◽  
pp. 75-81 ◽  
Author(s):  
MARC K. HALUSHKA ◽  
DEBRA J. MATHEWS ◽  
JEFFREY A. BAILEY ◽  
ARAVINDA CHAKRAVARTI
Keyword(s):  
Candidate Genes ◽  
Information Search ◽  
Complex Traits ◽  
Sequence Data ◽  
Query Point ◽  
Web Tool ◽  
Genetic Studies ◽  
Genomic Databases ◽  
Search Tool ◽  
Gene Information

Halushka, Marc K., Debra J. Mathews, Jeffrey A. Bailey, and Aravinda Chakravarti. GIST: A web tool for collecting gene information. Physiol. Genomics 1: 75–81, 1999.—As the human genome is sequenced and annotated, an important step in future genetic studies of complex traits and diseases will be the identification of relevant candidate genes. To enable such compilations, it would be useful to collate all necessary and available genetic information for each candidate gene. To this end, we have created a web tool ( http://genome.cwru.edu/gist/gist.html ) to allow the rapid cataloging of currently available genetic data. This tool, called GIST (or “Gene Information Search Tool”), allows an investigator to search the major genomic databases containing gene and marker information from a single query point. To prove the utility of GIST, a catalog of 150 hypertension candidate genes was created. This resource collates all available nucleotide and amino acid sequence data, expression data, chromosomal map location, and genetic marker interval for each gene, collected from on-line databases. These data can be used to guide genetic studies of hypertension.

scholarly journals TAMAL: an integrated approach to choosing SNPs for genetic studies of human complex traits

2006 ◽  
Vol 22 (5) ◽  
pp. 626-627 ◽  
Author(s):  
Bradley M. Hemminger ◽  
Billy Saelim ◽  
Patrick F. Sullivan
Keyword(s):  
Complex Traits ◽  
Integrated Approach ◽  
Genetic Studies ◽  
Human Complex

scholarly journals Empirical Evaluation of the Genetic Similarity of Samples From Twin Registries in Australia and the Netherlands Using 359 STRP Markers

2006 ◽  
Vol 9 (4) ◽  
pp. 600-602 ◽  
Author(s):  
Patrick F. Sullivan ◽  
Grant W. Montgomery ◽  
Jouke Jan Hottenga ◽  
Naomi R. Wray ◽  
Dorret I. Boomsma ◽  
...  
Keyword(s):  
Genetic Variability ◽  
The Netherlands ◽  
Tandem Repeat ◽  
Short Tandem Repeat ◽  
Complex Traits ◽  
Genetic Similarity ◽  
Empirical Evaluation ◽  
Twin Studies ◽  
Genetic Studies ◽  
Short Tandem

AbstractOne way to achieve the large sample sizes required for genetic studies of complex traits is to combine samples collected by different groups. It is not often clear, however, whether this practice is reasonable from a genetic perspective. To assess the comparability of samples from the Australian and the Netherlands twin studies, we estimated Fst (the proportion of total genetic variability attributable to genetic differences between cohorts) based on 359 short tandem repeat polymorphisms in 1068 individuals. Fst was estimated to be 0.30% between the Australian and the Netherlands cohorts, a smaller value than between many European groups. We conclude that it is reasonable to combine the Australian and the Netherlands samples for joint genetic analyses.

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