A cross-population atlas of genetic associations for 220 human phenotypes

Sakaue, Saori; Kanai, Masahiro; Tanigawa, Yosuke; Karjalainen, Juha; Kurki, Mitja; Koshiba, S.; Narita, Akira; Konuma, Takahiro; Yamamoto, Kenichi; Akiyama, Masato; Ishigaki, Kazuyoshi; Suzuki, Akari; Suzuki, Ken; Obara, Wataru; Yamaji, Katsuhiko; Takahashi, Kazuhisa; Asai, Satoshi; Takahashi, Yasuo; Suzuki, Takao; Shinozaki, Nobuaki; Yamaguchi, Hiroki; Minami, Shiro; Murayama, Shigeo; Yoshimori, Kozo; Nagayama, Satoshi; Obata, Daisuke; Higashiyama, Masahiko; Masumoto, Akihide; Koretsune, Yukihiro; FinnGen,; Ito, Kei; Terao, Chikashi; Yamauchi, Toshimasa; Komuro, Issei; Kadowaki, Takashi; Tamiya, Gen; Yamamoto, Masayuki; Nakamura, Yusuke; Kubo, Michiaki; Murakami, Yoshinori; Yamamoto, Kazuhiko; Kamatani, Yoichiro; Palotie, Aarno; Rivas, Manuel A.; Daly, Mark J.; Matsuda, Koichi; Okada, Yukinori

doi:10.1038/s41588-021-00931-x

Cited by 956 publications

(897 citation statements)

References 59 publications

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“…FOXA1/2 may program both pancreatic beta cells and ventral midbrain NPCs and use the same molecular tools (e.g., K-ATP subunit genes) in different tissue types to achieve different ends (presumably insulin secretion and regulation of calcium transients, respectively). Finally, Foxa2 is regulated by insulin itself (Wolfrum et al, 2003) and several single nucleotide polymorphisms (SNPs) in the gene are significantly associated with different metabolic indicators, such as fasting blood glucose levels [e.g., rs6048205 (Manning et al, 2012;Wojcik et al, 2019;Sinnott-Armstrong et al, 2021), rs3833331 (Chen et al, 2021;Sakaue et al, 2021), rs1209523 (Xing et al, 2010;Wojcik et al, 2019), rs72470563 (Chung et al, 2021), rs1337918 (Chen et al, 2021)].…”

Section: Part B: Developmental Programming Of Ventral Midbrain Da Cel...mentioning

confidence: 99%

“…The polymorphism rs10733682 is associated with BMI (Locke et al, 2015) and the AA genotype of rs10733682 interacts with intake of total energy, fat, and carbohydrate in determining risk of developing elevated triglycerides levels, which is associated with higher obesity incidence (Zhu et al, 2020). Numerous other LMX1B variants have been associated with BMI or fat body mass in genome-wide association studies, such as rs867559 (Speliotes et al, 2010), rs7027304 (Tachmazidou et al, 2017;Sakaue et al, 2021), rs3829849 (Costa-Urrutia et al, 2020, rs2235056 (Akiyama et al, 2017), rs1336980 (Vogelezang et al, 2020), rs7030609 and rs2275241 (Richardson et al, 2020).…”

Section: Part B: Developmental Programming Of Ventral Midbrain Da Cel...mentioning

confidence: 99%

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Evidence That Substantia Nigra Pars Compacta Dopaminergic Neurons Are Selectively Vulnerable to Oxidative Stress Because They Are Highly Metabolically Active

Ernst

2022

Front. Cell. Neurosci.

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There are 400–500 thousand dopaminergic cells within each side of the human substantia nigra pars compacta (SNpc) making them a minuscule portion of total brain mass. These tiny clusters of cells have an outsized impact on motor output and behavior as seen in disorders such as Parkinson’s disease (PD). SNpc dopaminergic neurons are more vulnerable to oxidative stress compared to other brain cell types, but the reasons for this are not precisely known. Here we provide evidence to support the hypothesis that this selective vulnerability is because SNpc neurons sustain high metabolic rates compared to other neurons. A higher baseline requirement for ATP production may lead to a selective vulnerability to impairments in oxidative phosphorylation (OXPHOS) or genetic insults that impair Complex I of the electron transport chain. We suggest that the energy demands of the unique morphological and electrophysiological properties of SNpc neurons may be one reason these cells produce more ATP than other cells. We further provide evidence to support the hypothesis that transcription factors (TFs) required to drive induction, differentiation, and maintenance of midbrain dopaminergic neural progenitor cells which give rise to terminally differentiated SNpc neurons are uniquely involved in both developmental patterning and metabolism, a dual function unlike other TFs that program neurons in other brain regions. The use of these TFs during induction and differentiation may program ventral midbrain progenitor cells metabolically to higher ATP levels, allowing for the development of those specialized cell processes seen in terminally differentiated cells. This paper provides a cellular and developmental framework for understanding the selective vulnerability of SNpc dopaminergic cells to oxidative stress.

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Section: Part B: Developmental Programming Of Ventral Midbrain Da Cel...mentioning

confidence: 99%

Section: Part B: Developmental Programming Of Ventral Midbrain Da Cel...mentioning

confidence: 99%

Evidence That Substantia Nigra Pars Compacta Dopaminergic Neurons Are Selectively Vulnerable to Oxidative Stress Because They Are Highly Metabolically Active

Ernst

2022

Front. Cell. Neurosci.

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“…Olink Explore targets 1,475 proteins, of which 300 are not targeted by SomaScan v4, including ITGA11. The minor allele of Val433Met in ITGA11 (rs2306022; MAF=9%) is the sentinel cis pQTL for ITGA11 ( p =2.1×10 -212 , effect=-0.36SD) and is reported to confer risk of Dupuytren contracture (OR=1.27) and uterine fibroids (OR=1.12) 18, 19 (Extended Data Figure 5). The fact that the variant associates with ITGA11 levels is a PAV, and not an eQTL, raises the concern that the observed reduction in ITGA11 may be the result of a probe binding artefact.…”

Section: Resultsmentioning

confidence: 99%

Large-scale comparison of immunoassay- and aptamer-based plasma proteomics through genetics and disease

Eldjárn

Ferkingstad

Lund

et al. 2022

Preprint

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High-throughput proteomics platforms measuring thousands of proteins in blood combined with genomic information have the power to bridge the gap between the genome and diseases and in that capture some of the environmental contributions to their risk and pathogenesis. Although such methods have already demonstrated their utility, the validation of their actual protein targets is lacking. Here we present a large-scale analysis of levels of proteins in plasma and protein quantitative trait loci (pQTLs) detected using the Olink Explore 1536 (1,459 immunoassays) in 47,151 European participants from the UK Biobank with 57.7 million imputed sequence variants. We compared the results with those of a large-scale SomaScan v4 study (35,559 participants and 4,907 aptamer-based assays) in order to assess and compare the qualities of these two platforms. The correlation between levels of proteins targeted by the two platforms is modest (median Spearman correlation 0.46). The vast majority of assays on the Olink Explore platform had cis pQTLs, evidence that they correctly target their intended proteins (84%), while the assays on the SomaScan v4 platform were half as likely to have cis pQTLs (38%). We also highlight novel pQTLs discovered using the Olink Explore platform, not captured by SomaScan v4, and describe their colocalization with disease-associated sequence variants as well as associations between protein levels and diseases. Our results further underscore the value of proteomics data and highlight the major differences in quality between the two most commonly used high-throughput proteomics platforms.

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“…Among the non-overlapping results, the most significant finding in the differential expression analysis of STIR volume was the negative correlation of CASC20 . This is a long non-coding RNA which function is still unknown, but variants in this gene have through GWAS been associated with height and body shape 49 , 50 . This is interesting, as related characteristics like BMI has been associated to MC 51 .…”

Section: Discussionmentioning

confidence: 99%

Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement

Flåm

Vigeland

Espeland

et al. 2022

Sci Rep

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Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifiable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood. We explored the pathobiology of these lesions using profiling of gene expression in blood, coupled with an edema-sensitive MRI technique known as short tau inversion recovery (STIR) imaging. STIR images and total RNA from blood were collected from 96 patients with chronic LBP and MC type I, the most inflammatory MC state. We found the expression of 37 genes significantly associated with STIR signal volume, ten genes with edema abundancy (a constructed combination of STIR signal volume, height, and intensity), and one gene with expression levels significantly associated with maximum STIR signal intensity. Gene sets related to interferon signaling, mitochondrial metabolism and defense response to virus were identified as significantly enriched among the upregulated genes in all three analyses. Our results point to inflammation and immunological defense as important players in MC biology in patients with chronic LBP.

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A cross-population atlas of genetic associations for 220 human phenotypes

Cited by 956 publications

References 59 publications

Evidence That Substantia Nigra Pars Compacta Dopaminergic Neurons Are Selectively Vulnerable to Oxidative Stress Because They Are Highly Metabolically Active

Evidence That Substantia Nigra Pars Compacta Dopaminergic Neurons Are Selectively Vulnerable to Oxidative Stress Because They Are Highly Metabolically Active

Large-scale comparison of immunoassay- and aptamer-based plasma proteomics through genetics and disease

Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement

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