Bench Research Informed by GWAS Results

Kondratyev, Nikolay; Алфимова, М. В.; Golov, Arkadiy K.; Голимбет, В. Е.

doi:10.3390/cells10113184

Cited by 7 publications

(6 citation statements)

References 253 publications

(271 reference statements)

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“…20 In addition, the impact of genetic variation on the outcome is chronological, that is, Mendelian randomization can solve the problem of reverse causality (Figure 1). 21 With the rapid development of genome-wide association studies (GWAS) recently, 22 it is much more convenient to obtain the genetic associations with both exposure and outcome, especially in the two-sample MR setting.…”

Section: Introductionmentioning

confidence: 99%

The causal effects of inflammatory bowel disease on primary biliary cholangitis: A bidirectional two‐sample Mendelian randomization study

Zhang

Chen

Fan

et al. 2023

Liver International

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Background Observational studies have indicated that the incidence of primary biliary cholangitis (PBC) is higher in inflammatory bowel disease (IBD) patients than that in healthy people. However, whether the correlation is causal remains unclear. Methods The genetic associations with IBD were obtained from publicly available genome‐wide association studies (GWAS) of European ancestry with 31 665 cases and 33 977 controls, consisting of 17 897 Crohn's disease (CD) and 13 768 ulcerative colitis (UC) cases. The genetic associations with PBC were obtained from a European GWAS with 2764 cases and 10 475 controls. A bidirectional two‐sample Mendelian randomization (MR) design was implemented to determine the causal relationship between IBD and PBC. In the forward MR, the IBD was treated as the exposure while the PBC was the exposure in the reverse MR. The inverse‐variance‐weighted (IVW) method was utilized as the main statistic method, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy. Results A total of 99 valid instrumental variables (IVs) were selected for IBD and the number of IVs for PBC was 18. The forward MR analysis indicated that genetically predicted IBD (UC and CD) was significantly associated with an increased risk of PBC (IVW OR = 1.343; 95% CI: 1.220–1.466). Similar casual associations were observed in UC (IVW OR = 1.244; 95% CI: 1.057–1.430) and CD (IVW OR = 1.269; 95% CI: 1.159–1.379). Such results were still consistent in multiple MR methods. The reverse MR analysis implicated that genetic susceptibility to PBC might not alter the risk of IBD (IVW OR = 1.070; 95% CI: 0.984–1.164). Conclusion Our study found that genetically predicted IBD can increase the risk of PBC while not vice versa in the European population, which may enlighten the aetiology of PBC, together with the IBD patient management.

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Section: Introductionmentioning

confidence: 99%

The causal effects of inflammatory bowel disease on primary biliary cholangitis: A bidirectional two‐sample Mendelian randomization study

Zhang

Chen

Fan

et al. 2023

Liver International

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“…Aun así, después habrá que realizar algunos análisis adicionales para confirmar que realmente es esta variante, y no otro SNP cercano que no haya sido estudiado, la que está relacionada con el rasgo (Uffelmann et al, 2021). Como ya se ha nombrado anteriormente, GWAS es actualmente la mejor técnica para detectar la adaptación local, además de ser una de las técnicas más utilizadas para los análisis genéticos que buscan relaciones entre genes y rasgos (Kondratyev et al, 2021). Sin embargo, esta técnica no es perfecta, y se ha topado con una dificultad en la detección que es difícil de superar, la identificación de marcas de selección sutiles en el genoma (Fu y Akey, 2013).…”

Section: Detección De Las Adaptaciones Localesunclassified

Genética y adaptaciones locales en humanos

González

Garcı́a

2022

ambiociencias

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Los humanos actualmente habitan prácticamente todo el planeta, existiendo poblaciones capaces de vivir en zonas glaciares, prominentes montañas o regiones dominadas por patógenos. A pesar de la gran cantidad de factores que dificultan su supervivencia, se ha visto que determinados grupos tienen una notable capacidad para subsistir en sus ambientes locales, mayor que la que tendría una persona de otra parte del planeta. Esta diferencia de aptitud tiene una base genética, y se denomina “adaptación local”. Durante las últimas décadas han surgido muchos estudios que tratan de encontrar esas variantes genéticas que permiten la adaptación de una población a su entorno local, para lo que se han desarrollado multitud de técnicas que comparan las tasas de cambios en el ADN en distintas especies, las frecuencias de alelos en distintas poblaciones, la asociación de una variante con un rasgo determinado, etc. En este artículo se nombran algunas de las técnicas más empleadas en los estudios de adaptación y, posteriormente, se comentan dos adaptaciones que permiten reconocer los importantes efectos que tiene la diversidad genética en distintos grupos de humanos.

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“…The complex genetic architecture of SZ includes common alleles, rare gene mutations, copy number variations, deletions, and chromosomal translocations. Genome-wide association studies (GWAS) have identified genetic variants associated with SZ [3] that have served as a comprehensive resource for further mechanistic studies [4]. GWAS [3,5,6] and recent genetic studies [7] linked a number of transcription factors (e.g., TCF4, PRDM14, POU5F1, TEAD1, ZEB2, FOXP1, ZNF804A, etc.…”

Section: Introductionmentioning

confidence: 99%

ASCL1 Is Involved in the Pathogenesis of Schizophrenia by Regulation of Genes Related to Cell Proliferation, Neuronal Signature Formation, and Neuroplasticity

Abashkin,

Karpov,

Kurishev

et al. 2023

IJMS

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Schizophrenia (SZ) is a common psychiatric neurodevelopmental disorder with a complex genetic architecture. Genome-wide association studies indicate the involvement of several transcription factors, including ASCL1, in the pathogenesis of SZ. We aimed to identify ASCL1-dependent cellular and molecular mechanisms associated with SZ. We used Capture-C, CRISPR/Cas9 systems and RNA-seq analysis to confirm the involvement of ASCL1 in SZ-associated pathogenesis, establish a mutant SH-SY5Y line with a functional ASCL1 knockout (ASCL1-del) and elucidate differentially expressed genes that may underlie ASCL1-dependent pathogenic mechanisms. Capture-C confirmed the spatial interaction of the ASCL1 promoter with SZ-associated loci. Transcriptome analysis showed that ASCL1 regulation may be through a negative feedback mechanism. ASCL1 dysfunction affects the expression of genes associated with the pathogenesis of SZ, as well as bipolar and depressive disorders. Genes differentially expressed in ASCL1-del are involved in cell mitosis, neuronal projection, neuropeptide signaling, and the formation of intercellular contacts, including the synapse. After retinoic acid (RA)-induced differentiation, ASCL1 activity is restricted to a small subset of genes involved in neuroplasticity. These data suggest that ASCL1 dysfunction promotes SZ development predominantly before the onset of neuronal differentiation by slowing cell proliferation and impeding the formation of neuronal signatures.

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Bench Research Informed by GWAS Results

Cited by 7 publications

References 253 publications

The causal effects of inflammatory bowel disease on primary biliary cholangitis: A bidirectional two‐sample Mendelian randomization study

The causal effects of inflammatory bowel disease on primary biliary cholangitis: A bidirectional two‐sample Mendelian randomization study

Genética y adaptaciones locales en humanos

ASCL1 Is Involved in the Pathogenesis of Schizophrenia by Regulation of Genes Related to Cell Proliferation, Neuronal Signature Formation, and Neuroplasticity

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