Emma Johnson
Washington University in St. Louis
7 active projects
Duplicate of Autozygosity and complex traits - a replication
Scientific Questions Being Studied
While it is difficult to study the effects of rare, recessive variants on an individual basis, a more feasible approach is to estimate the genome-wide burden of these variants. One such method involves estimating the proportion of the genome contained in runs of homozygosity (ROHs), which are stretches of DNA that are identical by descent (autozygous). ROHs increase the likelihood of observing the effects of rare, recessive variants, and a previous study from Clark et al. (2019) found that a greater level of FROH (the proportion of the genome contained in ROHs) was associated with lower values on 32 complex traits like height, weight, respiratory function, LDL cholesterol, and measures of fertility. We are interested in seeing if these associations are replicated in the All of Us dataset, as this is one of the largest and most diverse US cohorts studied to date.
Project Purpose(s)
- Ancestry
Scientific Approaches
I will calculate ROHs in All of Us individuals with genome-wide array data available, following the methods of our recent preprint (Colbert et al., https://doi.org/10.1101/2021.11.24.469902). I will then regress each complex trait on FROH, in a separate model for each trait. All models will control for covariates including age, sex, and genetic principal components.
Anticipated Findings
There is value in replicating past results, and it will be informative to know the extent to which Clark et al.'s meta-analyzed findings replicate in a large US cohort. This project could result in a better understanding of the extent to which rare, recessive variants contribute to risk of complex traits in a large, diverse US biobank.
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set Used
Controlled Tier
Duplicate of Genetics of substance use and substance use disorders
Scientific Questions Being Studied
We are affiliated with the Psychiatric Genomics Consortium Substance Use Disorders (PGC SUD) working group and our major goal is to better understand the genetic and biological factors underlying substance use disorders. This research may potentially lead to improved treatments and prevention efforts.
Project Purpose(s)
- Disease Focused Research (Substance use disorders and correlated psychiatric disorders)
- Ancestry
Scientific Approaches
We plan to use approaches such as genome-wide association analyses, polygenic risk score approaches, Mendelian randomization, GCTA, and other statistical genetics methods for analyzing SNP- and gene-based associations, generating polygenic predictors, estimating causal paths, and estimating heritability. We anticipate using the electronic health records data and other health- and behavior-related data in All of US. We will also be using the whole genome sequence data and the genotype array data, as well as the ancestry assignments and principal components provided by All of Us.
Anticipated Findings
We know that there are many genetic variants that contribute to substance use disorders (SUDs). Many of these variants exert effects on multiple SUDs (e.g., cannabis use disorder and tobacco use disorder), as well as other psychiatric disorders, while some variants seem to be substance-specific. We are still uncovering the gene networks and biological pathways implicated by these risk variants, and larger samples are still needed to detect common genetic risk variants, especially for under-represented populations in addiction genetic research. The All of Us Research Program provides a valuable resource for us to make progress on these questions and expand our research to include individuals of diverse ancestries. This research could eventually lead to better prevention methods and treatments for SUDs, and it is essential that all populations benefit from these findings.
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set Used
Controlled TierResearch Team
Owner:
- Joseph Deak - Research Fellow, Yale University
- Emma Johnson - Other, Washington University in St. Louis
Collaborators:
- Sarah Colbert - Project Personnel, Icahn School of Medicine at Mount Sinai
- Renato Polimanti - Mid-career Tenured Researcher, Yale University
- Howard Edenberg - Late Career Tenured Researcher, Indiana University
- Dongbing Lai - Project Personnel, Indiana University
- Alexander Hatoum - Research Fellow, Washington University in St. Louis
- Alex Miller - Research Fellow, Washington University in St. Louis
Autozygosity and complex traits - a replication
Scientific Questions Being Studied
While it is difficult to study the effects of rare, recessive variants on an individual basis, a more feasible approach is to estimate the genome-wide burden of these variants. One such method involves estimating the proportion of the genome contained in runs of homozygosity (ROHs), which are stretches of DNA that are identical by descent (autozygous). ROHs increase the likelihood of observing the effects of rare, recessive variants, and a previous study from Clark et al. (2019) found that a greater level of FROH (the proportion of the genome contained in ROHs) was associated with lower values on 32 complex traits like height, weight, respiratory function, LDL cholesterol, and measures of fertility. We are interested in seeing if these associations are replicated in the All of Us dataset, as this is one of the largest and most diverse US cohorts studied to date.
Project Purpose(s)
- Ancestry
Scientific Approaches
I will calculate ROHs in All of Us individuals with genome-wide array data available, following the methods of our recent preprint (Colbert et al., https://doi.org/10.1101/2021.11.24.469902). I will then regress each complex trait on FROH, in a separate model for each trait. All models will control for covariates including age, sex, and genetic principal components.
Anticipated Findings
There is value in replicating past results, and it will be informative to know the extent to which Clark et al.'s meta-analyzed findings replicate in a large US cohort. This project could result in a better understanding of the extent to which rare, recessive variants contribute to risk of complex traits in a large, diverse US biobank.
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set Used
Controlled TierAutozygosity and depression - controlled tier
Scientific Questions Being Studied
The role of common genetic variation on risk for depression has been well-characterized by GWAS, but the role of rare, recessive variants is unclear. Runs of homozygosity (ROH) provide one approach to estimate the overall burden of rare, recessive variants on complex traits, using only genotype array data. Findings on the association between ROHs and depression have been mixed, and most studies have been small and only included individuals of European ancestry. We aim to explore the effect of autozygosity (proportion of the genome contained in ROHs) on depression in All of Us, as this will be one of the largest and most diverse studies on the topic to date.
Project Purpose(s)
- Ancestry
Scientific Approaches
I will calculate ROHs in All of Us individuals with genome-wide array data available, following the methods of our recent preprint (Colbert et al., https://doi.org/10.1101/2021.11.24.469902), and regress depression on the proportion of the genome contained in ROHs. All models will control for covariates including age, sex, and genetic principal components.
Anticipated Findings
As mentioned above, some studies have found that individuals with greater autozygosity (proportion of the genome contained in ROHs) tend to have greater risk for depression, among other trait associations. Other studies have suggested that differences in ascertainment or other biases might contribute to these associations. Ultimately, this project could result in a better understanding of the extent to which rare, recessive variants contribute to risk of depression in a large, diverse biobank.
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set Used
Controlled TierAutozygosity and depression
Scientific Questions Being Studied
The role of common genetic variation on risk for depression has been well-characterized by GWAS, but the role of rare, recessive variants is unclear. Runs of homozygosity (ROH) provide one approach to estimate the overall burden of rare, recessive variants on complex traits, using only genotype array data. Findings on the association between ROHs and depression have been mixed, and most studies have been small and only included individuals of European ancestry. We aim to explore the effect of autozygosity (proportion of the genome contained in ROHs) on depression in All of Us, as this will be one of the largest and most diverse studies on the topic to date.
Project Purpose(s)
- Ancestry
Scientific Approaches
I will calculate ROHs in All of Us individuals with genome-wide array data available, following the methods of our recent preprint (Colbert et al., https://doi.org/10.1101/2021.11.24.469902), and regress depression on the proportion of the genome contained in ROHs. All models will control for covariates including age, sex, and genetic principal components.
Anticipated Findings
As mentioned above, some studies have found that individuals with greater autozygosity (proportion of the genome contained in ROHs) tend to have greater risk for depression, among other trait associations. Other studies have suggested that differences in ascertainment or other biases might contribute to these associations. Ultimately, this project could result in a better understanding of the extent to which rare, recessive variants contribute to risk of depression in a large, diverse biobank.
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set Used
Registered TierAutozygosity and suicidal thoughts and behaviors
Scientific Questions Being Studied
Suicidal thoughts and behaviors (STBs) are complex, transdiagnostic traits, with genetic (heritability=17-55%) and environmental factors contributing to liability. Much of the work on genetics of STBs has focused on latent genetic factors (twin/family studies) or variation at single nucleotide polymorphisms that are common in the population. Studying rare genetic variation typically requires very large samples with whole genome sequence data, something that is currently limited for studies of STBs. Runs of homozygosity (ROH) provide an alternative approach to estimate the overall impact of rare, recessive variants on complex traits, using only genotype array data. ROH are stretches of homozygous DNA that arise when an individuals’ parents share a common ancestor. We aim to explore the effect of autozygosity (proportion of the genome contained in ROH) on suicidal ideation in All of Us, as preliminary, exploratory research that may inform future grant proposals and research directions.
Project Purpose(s)
- Ancestry
Scientific Approaches
I will calculate ROH in All of Us individuals with genome-wide array data available, following the methods of our recent preprint (Colbert et al., https://doi.org/10.1101/2021.11.24.469902), and regress suicidal ideation on ROH. All models will control for covariates including age, sex, and genetic principal components. I will also compare the extent to which rare vs. common variants contribute to the relationship between homozygosity and suicidal ideation, contrasting ROH with other measures of homozygosity (e.g., correlation between uniting gametes).
Anticipated Findings
Some studies have found that individuals with greater autozygosity (proportion of the genome contained in ROH) tend to have lower cognitive ability and greater risk for depression, among other trait associations. Studies have also successfully used ROH to map recessive variants and risk genes in Alzheimer’s disease and alcohol use disorders. However, a literature search identified only one prior study on the association between autozygosity and STBs. Ultimately, this project could result in a better understanding of the extent to which rare, recessive variants contribute to risk of STBs.
As mentioned above, our analyses are exploratory and will be used to assess the feasibility of this approach for studying STBs in more extensive analyses in the future, acknowledging that our statistical power will be low, given small case numbers in the All of Us sample.
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set Used
Controlled TierResearch Team
Owner:
- Emma Johnson - Other, Washington University in St. Louis
Collaborators:
- Sarah Colbert - Project Personnel, Icahn School of Medicine at Mount Sinai
Changes in autozygosity over time
Scientific Questions Being Studied
Previous studies have linked higher levels of autozygosity - the proportion of the genome contained in runs of homozygosity (ROH) that are identical by descent - with worse outcomes on several fitness-related traits, including e.g., respiratory function and reproductive characteristics, such as number of children born. In a recently submitted study on ~6,500 adolescents (currently a preprint on biorxiv: https://doi.org/10.1101/2021.11.24.469902), we observed an unexpectedly low level of autozygosity in this sample compared to what had been described in previous studies of autozygosity. We suspect that generational differences in mean autozygosity, with an average decrease in autozygosity over time, might be the cause of this unexpectedly low level of autozygosity. We are currently testing this hypothesis in the UK Biobank and several US-based cohorts, and the addition of All of Us data would substantially increase our statistical power, especially for diverse populations.
Project Purpose(s)
- Ancestry
Scientific Approaches
We are currently testing the association between autozygosity and year of birth in both UK and US-based cohorts of all available ancestries using standard data analysis tools.
Following the ROH-calling procedures in Clark et al. (2019; https://doi.org/10.1038/s41467-019-12283-6), we use PLINK to QC genotype array data (not imputed) and call ROHs based on the following parameters: --homozyg-window-snp 50; --homozyg-snp 50; --homozyg-kb 1500; --homozyg-gap 1000; --homozyg-density 50; --homozyg-window-missing 5; homozyg-window-het 1
We then test the association between Froh (the proportion of the genome contained in ROHs, a proxy for autozygosity) and year of birth using linear regression implemented in R, controlling for sex and 10 genetic ancestry principal components as covariates. Analyses are conducted within genetic ancestries within cohorts, and then meta-analyzed across cohorts and ancestries.
Anticipated Findings
A study from Nalls et al. (2009) previously explored this phenomenon, finding that autozygosity steadily declined in relation to birth year, at a rate of 0.1% decrease in Froh for every 20 years decrease in chronological age. However, this study was a relatively small sample (N = 809) and only analyzed North Americans of European descent. Aside from Nalls et al. (2009), there seem to be few mentions of this phenomenon in the literature, except for an analysis of ancient DNA samples which found decreasing Froh over 1000s of years during the Holocene (Ceballos et al., 2021). We anticipate finding that mean levels of autozygosity decrease over generational time, in both US and UK samples of diverse ancestries. To our knowledge, this would be the largest demonstration of decreasing autozygosity over time in the modern era.
Demographic Categories of Interest
This study will not center on underrepresented populations.
Data Set Used
Controlled TierResearch Team
Owner:
- Emma Johnson - Other, Washington University in St. Louis
Collaborators:
- Sarah Colbert - Project Personnel, Icahn School of Medicine at Mount Sinai
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