Making the case for more inclusive GWAS

Clyde, Dorothy

doi:10.1038/s41576-019-0160-0

Cited by 9 publications

(7 citation statements)

References 2 publications

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“…First, the analyses only included youth of European ancestry to match the original training sample for the GWAS-derived DEP-PRS, thereby limiting the extent to which current findings can be generalized to youth of other racial identities. As the vast majority of GWAS are limited to European samples (Duncan, Shen, et al, 2019), it is of vital importance that future GWAS include samples of increased racial diversity to allow for generalization of results to marginalized racial and ethnic populations (Clyde, 2019). Second, the current sample size is not large by the standards of genetic studies and may have been underpowered to detect smaller main or interaction effects.…”

Section: Discussionmentioning

confidence: 99%

Associations between depression-relevant genetic risk and youth stress exposure: Evidence of gene–environment correlations.

Feurer¹,

McGeary²,

Brick³

et al. 2022

Journal of Psychopathology and Clinical Science

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Familial risk for depression is associated with youth exposure to self-generated dependent stressful life events and independent events that are out of youth’s control. Familial risk includes both genetic and environmental influences, raising the question of whether genetic influences, specifically, are associated with youth exposure to both dependent and independent stressful life events. To address this question, this study examined the relation between a genome-wide association study (GWAS)-derived depression-based polygenic risk score (DEP-PRS) and youth experiences of dependent and independent stress. Participants were 180 youth (ages 8 to 14, 52.2% female) of European ancestry and their biological mothers recruited based on the presence versus absence of a history of major depressive disorder (MDD) in the mothers. Youth and mothers were interviewed every 6 months for 2 years regarding the occurrence of stressful life events, which were coded as independent or dependent (self-generated). Results indicated that youth’s DEP-PRS and maternal history of MDD were uniquely associated with increased exposure to both dependent and independent events. Similar results were observed when examining major versus minor events separately, with the additional finding of a DEP-PRS × mother MDD interaction for major dependent events such that levels of moderate to severe dependent life stressors were highest among youth with high DEP-PRSs who also had mothers with MDD. These results not only support the presence of depression-relevant gene–environment correlations (rGEs), but also highlight the possibility that rather than only capturing depression-specific genetic liability, GWAS-derived polygenic risk scores may also capture genetic variance contributing to stress exposure.

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Section: Discussionmentioning

confidence: 99%

Associations between depression-relevant genetic risk and youth stress exposure: Evidence of gene–environment correlations.

Feurer¹,

McGeary²,

Brick³

et al. 2022

Journal of Psychopathology and Clinical Science

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“…Genetic ancestry plays an important role in genetic studies, especially when the genetic architecture differs between samples and results obtained from one population may not generalize to others [53][54][55][56] . The detection of epistatic signals could be affected by the possible existence of complex higher-order (>2 SNPs) interactions, genetic heterogeneity, and varying patterns of genetic architecture 57 .…”

Section: Discussionmentioning

confidence: 99%

Genome-wide epistasis analysis in Parkinson’s disease between populations with different genetic ancestry reveals significant variant-variant interactions

Cisterna-García

Bustos²,

Bandrés‐Ciga

et al. 2022

Preprint

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Genome-wide association studies (GWAS) have increased our understanding of Parkinson's disease (PD) genetics through the identification of common disease-associated variants. However, much of the heritability remains unaccounted for and we hypothesized that this could be partly explained by epistasis. Here, we developed a genome-wide non-exhaustive epistasis screening pipeline called Variant-variant interaction through variable thresholds (VARI3) and applied it to diverse PD GWAS cohorts. First, as a discovery cohort, we used 14 cohorts of European ancestry (14,671 cases and 17,667 controls) to identify candidate variant-variant interactions. Next, we replicated significant results in a cohort with a predominately Latino genetic ancestry (807 cases and 690 controls). We identified 14 significant epistatic signals in the discovery stage, with genes showing enrichment in PD-relevant ontologies and pathways. Next, we successfully replicated two of the 14 interactions, where the signals were located nearby SNCA and within MAPT and WNT3. Finally, we determined that the epistatic effect on PD of those variants was similar between populations. In brief, we identified several epistatic signals associated with PD and replicated associations despite differences in the genetic ancestry between cohorts. We also observed their biological relevance and effect on the phenotype using in silico analysis.

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“…For example, in contrast to our expectations, we did not find an association with the score for coronary artery disease, which is a major cause of NCDs (Lloyd-Jones et al 2006). Another important limitation, which is endemic to the GWAS literature (Clyde 2019; Mills and Rahal 2019), is that we did not study individuals of non-European ancestry. Thus, we do not know whether our findings generalize to other ancestries (Martin et al 2019, 2017).…”

Section: Discussionmentioning

confidence: 99%

Genetic risk scores of disease and mortality capture differences in longevity, economic behavior, and insurance outcomes

Linnér¹,

Koellinger²

2020

Preprint

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Widespread genetic testing for diseases may cause adverse selection, escalating premiums, or discrimination in various insurance markets. Here, without systematically informing study participants of their genetic predisposition, we estimate to what extent genetic data are informative about differences in longevity, health expectations, and economic behavior. We compute measures of genetic liability (polygenic scores) for 27 common diseases and mortality risks in 9,272 participants of the Health and Retirement Study (HRS). Survival analysis suggests that the highest decile of cumulative genetic risk can distinguish a median lifespan up to 4.5 years shorter, a difference that is similar to or larger than that distinguished by conventional actuarial risk factors, including sex. Furthermore, greater genetic liability is associated with less long-term care insurance, among other economic behaviors. We conclude that the rapid developments in genetic epidemiology pose new challenges for regulating consumer genetics and insurance markets, requiring urgent attention from policymakers.

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Making the case for more inclusive GWAS

Cited by 9 publications

References 2 publications

Associations between depression-relevant genetic risk and youth stress exposure: Evidence of gene–environment correlations.

Associations between depression-relevant genetic risk and youth stress exposure: Evidence of gene–environment correlations.

Genome-wide epistasis analysis in Parkinson’s disease between populations with different genetic ancestry reveals significant variant-variant interactions

Genetic risk scores of disease and mortality capture differences in longevity, economic behavior, and insurance outcomes

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