Genome-wide association studies: the good, the bad and the ugly

Frayling, TM

doi:10.7861/clinmedicine.14-4-428

Cited by 30 publications

(25 citation statements)

References 31 publications

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“…Rare mutations in this gene are also linked with low birth weight in the DECIPHER database [29] (https://decipher.sanger.ac.uk/gene/GNAS#overview/clinical-info), but the closest birth weight SNP to GNAS is 142,178bp away, within the NPEPL1 gene ( Figure 3). These findings support the hypothesis that the nearest gene to a SNP identified via GWAS may not always be the biologically relevant gene [30]. Syndromes resulting in large changes in birth weight associated with both of these developmental disorder genes also feature disorders of imprinting.…”

Section: Discussionsupporting

confidence: 76%

Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

Beaumont

Mayne

Freathy

et al. 2020

Preprint

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AbstractBirth weight is an important factor in newborn and infant survival, and both low and high birth weights are associated with adverse later life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with either maternal or fetal effects on birth weight. Knowledge of the underlying causal genes and pathways is crucial to understand how these loci influence birth weight, and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme upper or lower ends of the normal distribution, and genes implicated in those syndromes may provide valuable information to help prioritise candidate genes at GWAS loci. We examined the proximity of genes implicated in developmental disorders to birth weight GWAS loci at which a fetal effect is either likely or cannot be ruled out. We used simulations to test whether those genes fall disproportionately close to the GWAS loci. We found that birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected by chance. This is the case both when the developmental disorder gene is the nearest gene to the birth weight SNP and also when examining all genes within 258kb of the SNP. This enrichment was driven by genes that cause monogenic developmental disorders with dominant modes of inheritance. We found several examples of SNPs located in the intron of one gene that mark plausible effects via different nearby genes implicated in monogenic short stature, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight loci, which has helped identify GWAS loci likely to have direct fetal effects on birth weight which could not previously be classified as fetal or maternal due to insufficient statistical power.

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Section: Discussionsupporting

confidence: 76%

Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

Beaumont

Mayne

Freathy

et al. 2020

Preprint

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“…After these variants—single nucleotide polymorphisms (SNPs)—are identified, further analysis associates them with disease. GWAS are challenged by the fact that associated variants cannot be proven to be causative in the disease process [ 33 ]. Additionally, in the case of a disease with a complex inheritance pattern like POAG, single genetic variants may have limited value in assessing risk.…”

Section: Discussionmentioning

confidence: 99%

Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

Zukerman

Harris

Vercellin

et al. 2020

Genes

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Glaucoma, the world’s leading cause of irreversible blindness, is a complex disease, with differential presentation as well as ethnic and geographic disparities. The multifactorial nature of glaucoma complicates the study of genetics and genetic involvement in the disease process. This review synthesizes the current literature on glaucoma and genetics, as stratified by glaucoma subtype and ethnicity. Primary open-angle glaucoma (POAG) is the most common cause of glaucoma worldwide, with the only treatable risk factor (RF) being the reduction of intraocular pressure (IOP). Genes associated with elevated IOP or POAG risk include: ABCA1, AFAP1, ARHGEF12, ATXN2, CAV1, CDKN2B-AS1, FOXC1, GAS7, GMDS, SIX1/SIX6, TMCO1, and TXNRD2. However, there are variations in RF and genetic factors based on ethnic and geographic differences; it is clear that unified molecular pathways accounting for POAG pathogenesis remain uncertain, although inflammation and senescence likely play an important role. There are similar ethnic and geographic complexities in primary angle closure glaucoma (PACG), but several genes have been associated with this disorder, including MMP9, HGF, HSP70, MFRP, and eNOS. In exfoliation glaucoma (XFG), genes implicated include LOXL1, CACNA1A, POMP, TMEM136, AGPAT1, RBMS3, and SEMA6A. Despite tremendous progress, major gaps remain in resolving the genetic architecture for the various glaucoma subtypes across ancestries. Large scale carefully designed studies are required to advance understanding of genetic loci as RF in glaucoma pathophysiology and to improve diagnosis and treatment options.

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“…Two-sample MR analysis with multiple genetic variants as instrumental variables using summarized data was performed in our study to assess the causal relationship and its strength between BMI and AD 36 . The MR analysis was performed in both directions to establish the direction of causality between BMI and AD.…”

Section: Methodsmentioning

confidence: 99%

Investigating causal relationships between Body Mass Index and risk of atopic dermatitis: a Mendelian randomization analysis

Yew

Loh

Thng

et al. 2020

Sci Rep

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Population studies suggest that atopic dermatitis (AD) is associated with an increased risk of obesity, however a causal relationship between these two conditions remains to be established. We therefore use Mendelian randomization (MR) to evaluate whether obesity and AD are causally interlinked. We used summary statistics extracted from genome wide association studies of Body Mass Index (BMI) and AD. MR analysis was performed in both directions to establish the direction of causality between BMI and AD. We find that genetically determined increase in adiposity is associated with increased risk of AD (odds ratio of AD 1.08 [95% CI 1.01 to 1.14; p = 0.015] per unit increase in BMI). Conversely, genetically determined increased risk of AD is not associated with a higher BMI (change in BMI attributable to AD based on genetic information: 0.00; 95% CI − 0.02 to 0.02; p = 0.862). There was no evidence for confounding of these genetic analyses by horizontal pleiotropy. Our results indicate that the association of AD with obesity is likely to reflect a causal role for adiposity in the development of AD. Our findings enhance understanding of the etiology of AD, and the basis for experimental studies to evaluate the mechanistic pathways by which adiposity promotes AD.

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Genome-wide association studies: the good, the bad and the ugly

Cited by 30 publications

References 31 publications

Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

Investigating causal relationships between Body Mass Index and risk of atopic dermatitis: a Mendelian randomization analysis

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