Precision Medicine Advancements Using Whole Genome Sequencing, Noninvasive Whole Body Imaging, and Functional Diagnostics

Hou, Yu-Chih; H, Yu; Martin, R. Torrence; Nm, Schenker-Ahmed; Hicks, Michael A.; Et, Cirulli; Cohen,; Tj, Jönsson; Heister, R; Napier, Lori A.; Cl, Swisher; Dominguez, S; Tang, Haibao; Li, Wei; Barea, Jaime; Rybak, Christina; Smith, Erica D.; K, Duchicela; Doney, Michael; Brar, Pamila; Hernandez, N; Ef, Kirkness; Am, Kahn; Jc, Venter; Ds, Karow; Ct, Caskey

doi:10.1101/497560

Cited by 3 publications

(1 citation statement)

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“…More broadly, the case of SLC30A10 fits a pattern of discoveries of recent discoveries showing that recessive Mendelian disease symptoms can manifest in heterozygous carriers of deleterious variants, blurring the distinction between recessive and dominant disease genes and bridging the gap between common and rare disease genetics 79,80 . These discoveries are possible only by combining massive, biobank-scale genotype and phenotype datasets such as the UK Biobank.…”

Section: Clinical Relevance: Genome Interpretationmentioning

confidence: 86%

GWAS of serum ALT and AST reveals an association ofSLC30A10Thr95Ile with hypermanganesemia symptoms

Ward

Quenneville

et al. 2020

Preprint

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22To better understand molecular pathways underlying liver health and disease, we performed 23 genome-wide association studies (GWAS) on circulating levels of alanine aminotransferase (ALT) 24 and aspartate aminotransferase (AST) across 408,300 subjects from four ethnic groups in the UK 25 Biobank, focusing on variants associating with both enzymes. Of these variants, the strongest 26 effect is a rare (MAF in White British = 0.12%) missense variant in the gene encoding manganese 27 efflux transporter SLC30A10, Thr95Ile (rs188273166), associating with a 5.9% increase in ALT 28 and a 4.2% increase in AST. Carriers have higher prevalence of all-cause liver disease (OR = 1.70; 29 95% CI = 1.24 to 2.34) and higher prevalence of extrahepatic bile duct cancer (OR = 23.8; 95% 30 CI = 9.1 to 62.1) compared to non-carriers. Over 4% of the cases of extrahepatic 31 cholangiocarcinoma in the UK Biobank carry SLC30A10 Thr95Ile. Unlike variants in SLC30A10 32 known to cause the recessive syndrome hypermanganesemia with dystonia-1 (HMNDYT1), the 33 Thr95Ile variant has a detectable effect even in the heterozygous state. Also unlike HMNDYT1-34 causing variants, Thr95Ile results in a protein that is properly trafficked to the plasma membrane 35 when expressed in HeLa cells. These results suggest that coding variation in SLC30A10 impacts 36 liver health in more individuals than the small population of HMNDYT1 patients. 37 are sensitive biomarkers of liver injury; in particular, alanine aminotransferase (ALT) and aspartate 44 aminotransferase (AST) are released into the circulation during damage to hepatocyte 45 membranes 1,2 . One powerful approach for understanding the molecular basis of liver disease has 46 been to perform genome-wide association studies (GWAS) of levels of circulating liver enzymes 47 across large population samples 1,3-13 . Combined GWAS of ALT and AST have previously revealed 48 genetic associations providing potential therapeutic targets for liver disease such as PNPLA3 14 and 49HSD17B13 15 . To further study the genetics of hepatocellular damage, we performed GWAS on 50 circulating levels of ALT and AST in 408,300 subjects, meta-analyzed across four ethnic groups 51 in the UK Biobank. 52 Results 53 GWAS summary 54We performed a GWAS of ALT and AST in four sub-populations in the UK Biobank (Asian or 55 Asian British, Black or Black British, Chinese, and Black or Black British; sample sizes, number 56 of variants tested, and lGC values, Supplementary Table 1; genome-wide significant associations, 57 Supplementary Table 2; Manhattan and QQ plots for each enzyme and sub-population, 58 Supplementary Figures 1 and 2). After meta-analyzing across sub-populations to obtain a single 59 set of genome-wide p-values for each enzyme (Manhattan plots, Figure 1), we found 244 and 277 60 independent loci associating at p < 5 x 10 -8 with ALT and AST, respectively, defined by lead SNPs 61 separated by at least 500 kilobases and pairwise linkage disequilibrium (LD) r 2 less than 0.2. 62Enzyme levels were strongly associated w...

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Section: Clinical Relevance: Genome Interpretationmentioning

confidence: 86%

GWAS of serum ALT and AST reveals an association ofSLC30A10Thr95Ile with hypermanganesemia symptoms

Ward

Quenneville

et al. 2020

Preprint

View full text Add to dashboard Cite

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GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

Ward

Quenneville

et al. 2021

Nat Commun

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Understanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

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100 Years of evolving gene–disease complexities and scientific debutants

Zeeshan

Xiong

Liang

et al. 2019

Briefings in Bioinformatics

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It’s been over 100 years since the word `gene’ is around and progressively evolving in several scientific directions. Time-to-time technological advancements have heavily revolutionized the field of genomics, especially when it’s about, e.g. triple code development, gene number proposition, genetic mapping, data banks, gene–disease maps, catalogs of human genes and genetic disorders, CRISPR/Cas9, big data and next generation sequencing, etc. In this manuscript, we present the progress of genomics from pea plant genetics to the human genome project and highlight the molecular, technical and computational developments. Studying genome and epigenome led to the fundamentals of development and progression of human diseases, which includes chromosomal, monogenic, multifactorial and mitochondrial diseases. World Health Organization has classified, standardized and maintained all human diseases, when many academic and commercial online systems are sharing information about genes and linking to associated diseases. To efficiently fathom the wealth of this biological data, there is a crucial need to generate appropriate gene annotation repositories and resources. Our focus has been how many gene–disease databases are available worldwide and which sources are authentic, timely updated and recommended for research and clinical purposes. In this manuscript, we have discussed and compared 43 such databases and bioinformatics applications, which enable users to connect, explore and, if possible, download gene–disease data.

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Precision Medicine Advancements Using Whole Genome Sequencing, Noninvasive Whole Body Imaging, and Functional Diagnostics

Cited by 3 publications

References 79 publications

GWAS of serum ALT and AST reveals an association ofSLC30A10Thr95Ile with hypermanganesemia symptoms

GWAS of serum ALT and AST reveals an association ofSLC30A10Thr95Ile with hypermanganesemia symptoms

GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

100 Years of evolving gene–disease complexities and scientific debutants

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