Exploring the Genetic Correlation Between Growth and Immunity Based on Summary Statistics of Genome-Wide Association Studies

Zhang, Zhe; Ma, Peipei; Li, Qiumeng; Xiao, Qiang; Sun, Hao; Olasege, Babatunde Shittu; Wang, Qishan; Pan, Yuchun

doi:10.3389/fgene.2018.00393

Cited by 11 publications

(8 citation statements)

References 67 publications

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“…We have used the state-of-the-art statistical methods for assessing genetic correlation, using publicly available summary statistics of genetic associations. This method has been previously used to assess genetic correlations for example between 24 traits (including cardio-metabolic traits, mental health disorders, inflammatory bowel disease and educational attainment but not respiratory conditions) [ 26 ], between thirteen growth and eleven immune phenotypes (including asthma) [ 32 ], and between six cancers (including lung) and 14 non-cancer diseases (not respiratory conditions) [ 33 ]. To our knowledge, this method has not been used to report genetic correlations between cardio-metabolic traits and lung function measures as shown here.…”

Section: Discussionmentioning

confidence: 99%

Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment

et al. 2021

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Background Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors. Methods We performed three analyses: (1) cardio-metabolic health to lung function association tests in Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies (N > 82,000). Results We observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure. Conclusions The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.

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Section: Discussionmentioning

confidence: 99%

Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment

et al. 2021

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“…One of the most pleotropic variants in the human genome is rs13107325 (C → T), a missense variant in SLC39A8 that results in a substitution of threonine for alanine at position 391 (A391T) in exon 8. The minor allele (T) is associated with increased risk of schizophrenia 1 as well as more than 30 unique traits including: changes in immune and growth traits 2 , increased HDL 3 , increased risk of inflammatory bowel disease and severe idiopathic scoliosis 4 , and decreased serum manganese (Mn) 5 , diastolic blood pressure 6 , fluid intelligence 7 , neurodevelopmental outcomes 8 , grey matter volume in multiple brain regions 9 , and Parkinson’s disease risk 10 . The minor allele (T) of rs13107325 occurs at a frequency of ~ 8% in those of European descent, with lower frequencies in Asian and African populations 11 .…”

Section: Introductionmentioning

confidence: 99%

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

Mealer

Jenkins

Chen

et al. 2020

Sci Rep

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A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers.

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“…A range of secondary analyses of GWAS data can be conducted to further probe the relevant genetic architecture 23 . Such analyses include determining the portion of heritability conferred by the SNPs investigated in a GWAS, defined as SNP-based heritability ( h 2 SNP ) 24 , estimating the degree of shared genetic architecture between disorders by determining their genetic correlation 25 , 26 , calculating PRSs based on risk variants for a disorder identified in a GWAS 27 , and undertaking enrichment analysis to assess clustering of detected variants within functionally related genomic regions and biological pathways 28 .…”

Section: Genome Variantsmentioning

confidence: 99%

Cutting-edge genetics in obsessive-compulsive disorder

Saraiva¹,

Cappi²,

Simpson³

et al. 2020

Fac Rev

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This article reviews recent advances in the genetics of obsessive-compulsive disorder (OCD). We cover work on the following: genome-wide association studies, whole-exome sequencing studies, copy number variation studies, gene expression, polygenic risk scores, gene–environment interaction, experimental animal systems, human cell models, imaging genetics, pharmacogenetics, and studies of endophenotypes. Findings from this work underscore the notion that the genetic architecture of OCD is highly complex and shared with other neuropsychiatric disorders. Also, the latest evidence points to the participation of gene networks involved in synaptic transmission, neurodevelopment, and the immune and inflammatory systems in this disorder. We conclude by highlighting that further study of the genetic architecture of OCD, a great part of which remains to be elucidated, could benefit the development of diagnostic and therapeutic approaches based on the biological basis of the disorder. Studies to date revealed that OCD is not a simple homogeneous entity, but rather that the underlying biological pathways are variable and heterogenous. We can expect that translation from bench to bedside, through continuous effort and collaborative work, will ultimately transform our understanding of what causes OCD and thus how best to treat it.

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Exploring the Genetic Correlation Between Growth and Immunity Based on Summary Statistics of Genome-Wide Association Studies

Cited by 11 publications

References 67 publications

Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment

Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

Cutting-edge genetics in obsessive-compulsive disorder

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