Methods for the Analysis and Interpretation for Rare Variants Associated with Complex Traits

Weissenkampen, J. Dylan; Jiang, Yu; Eckert, Scott; Jiang, Bibo; Li, Bingshan; Liu, Dajiang

doi:10.1002/cphg.83

Cited by 12 publications

(18 citation statements)

References 108 publications

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“…Therefore, the likelihood of disease-causing effect of identified variants was assessed in our study by established bioinformatic tools for genetics and by assessing the genotype-phenotype correlation in each patient with current knowledge from literature and databases in the field. In future studies with bigger sample size, next-generation statistical genetic analyses may be employed to identify associations between a group of variants and the complex trait of sex development (Weissenkampen et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Broad Phenotypes of Disorders/Differences of Sex Development in MAMLD1 Patients Through Oligogenic Disease

et al. 2019

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Disorders/differences of sex development (DSD) are the result of a discordance between chromosomal, gonadal, and genital sex. DSD may be due to mutations in any of the genes involved in sex determination and development in general, as well as gonadal and/or genital development specifically. MAMLD1 is one of the recognized DSD genes. However, its role is controversial as some MAMLD1 variants are present in normal individuals, several MAMLD1 mutations have wild-type activity in functional studies, and the Mamld1 -knockout male mouse presents with normal genitalia and reproduction. We previously tested nine MAMLD1 variants detected in nine 46,XY DSD patients with broad phenotypes for their functional activity, but none of the mutants, except truncated L210X, had diminished transcriptional activity on known target promoters CYP17A1 and HES3 . In addition, protein expression of MAMLD1 variants was similar to wild-type, except for the truncated L210X. We hypothesized that MAMLD1 variants may not be sufficient to explain the phenotype in 46,XY DSD individuals, and that further genetic studies should be performed to search for additional hits explaining the broad phenotypes. We therefore performed whole exome sequencing (WES) in seven of these 46,XY patients with DSD and in one 46,XX patient with ovarian insufficiency, who all carried MAMLD1 variants. WES data were filtered by an algorithm including disease-tailored lists of MAMLD1 -related and DSD-related genes. Fifty-five potentially deleterious variants in 41 genes were identified; 16/55 variants were reported in genes in association with hypospadias, 8/55 with cryptorchidism, 5/55 with micropenis, and 13/55 were described in relation with female sex development. Patients carried 1-16 variants in 1-16 genes together with their MAMLD1 variation. Network analysis of the identified genes revealed that 23 genes presented gene/protein interactions with MAMLD1. Thus, our study shows that the broad phenotypes of individual DSD might involve multiple genetic variations contributing towards the complex network of sexual development.

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Section: Discussionmentioning

confidence: 99%

Broad Phenotypes of Disorders/Differences of Sex Development in MAMLD1 Patients Through Oligogenic Disease

et al. 2019

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“…The first involves testing whether a specific gene has an increased burden of rare mutations in patients with EoE compared with control subjects. [8][9][10] The second approach is to evaluate whether a specific rare variant co-occurs with disease in families in which many members have the disease. [11][12][13] For both rare variant approaches, analytic filtering approaches are used to narrow down the considered variants.…”

Section: Type 1 Errormentioning

confidence: 99%

The genetic etiology of eosinophilic esophagitis

Kottyan

Parameswaran

Weirauch

et al. 2020

Journal of Allergy and Clinical Immunology

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Eosinophilic esophagitis (EoE) is a chronic allergic disease associated with marked mucosal eosinophil accumulation. Multiple studies have reported a strong familial component to EoE, with the presence of EoE increasing the risk for other family members with EoE. Epidemiologic studies support an important role for environmental risk factors as modulators of genetic risk. In a small percentage of cases, including patients who have Mendelian diseases with co-occurrent EoE, rare genetic variation with large effect sizes could mediate EoE and explain multigenerational incidence in families. Common genetic risk variants mediate genetic risk for the majority of patients with EoE. Across the 31 reported independent EoE risk loci (P < 10 25), most of the EoE risk variants are located in between genes (36.7%) or within the introns of genes (42.4%). Although some variants do change the amino acid sequence of genes (2.2%), only 3 of the 31 EoE risk loci harbor an amino acid-changing variant. Thus most EoE risk loci are outside of the coding regions of genes, suggesting a key role for gene regulation in patients with EoE, which is consistent with most other complex diseases. (J Allergy Clin Immunol 2020;145:9-15.)

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“…These complexities make it difficult to understand how GWAS loci contribute to their associated traits and have significantly hampered the interpretation and application of GWAS results. To address this, many different fine-mapping approaches have been developed in the post-GWAS era with the aim of identifying the important variants and genes and interpreting their biological impact on diseases and traits [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

A practical view of fine-mapping and gene prioritization in the post-genome-wide association era

2020

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Over the past 15 years, genome-wide association studies (GWASs) have enabled the systematic identification of genetic loci associated with traits and diseases. However, due to resolution issues and methodological limitations, the true causal variants and genes associated with traits remain difficult to identify. In this post-GWAS era, many biological and computational fine-mapping approaches now aim to solve these issues. Here, we review fine-mapping and gene prioritization approaches that, when combined, will improve the understanding of the underlying mechanisms of complex traits and diseases. Fine-mapping of genetic variants has become increasingly sophisticated: initially, variants were simply overlapped with functional elements, but now the impact of variants on regulatory activity and direct variant-gene 3D interactions can be identified. Moreover, gene manipulation by CRISPR/Cas9, the identification of expression quantitative trait loci and the use of co-expression networks have all increased our understanding of the genes and pathways affected by GWAS loci. However, despite this progress, limitations including the lack of cell-type- and disease-specific data and the ever-increasing complexity of polygenic models of traits pose serious challenges. Indeed, the combination of fine-mapping and gene prioritization by statistical, functional and population-based strategies will be necessary to truly understand how GWAS loci contribute to complex traits and diseases.

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Methods for the Analysis and Interpretation for Rare Variants Associated with Complex Traits

Cited by 12 publications

References 108 publications

Broad Phenotypes of Disorders/Differences of Sex Development in MAMLD1 Patients Through Oligogenic Disease

Broad Phenotypes of Disorders/Differences of Sex Development in MAMLD1 Patients Through Oligogenic Disease

The genetic etiology of eosinophilic esophagitis

A practical view of fine-mapping and gene prioritization in the post-genome-wide association era

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