Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts

Cirulli, Elizabeth T.; White, Simon; Read, Robert W.; Elhanan, Gai; Metcalf, William J.; Tanudjaja, Francisco; Fath, Donna M.; Sandoval, Efren; Isaksson, Magnus; Schlauch, Karen; Grzymski, Joseph J.; Lu, James T.; Washington, Nicole

doi:10.1038/s41467-020-14288-y

Cited by 127 publications

(167 citation statements)

References 60 publications

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“…In addition to the coding ZIP12 polymorphisms, rare variant carriers in ZIP12 have differences in caudate, putamen, and pallidum swMRI. Using resources established by Cirulli et al, 56 there were 36 heterozygote carriers of the ZIP12 variants present in 9565 subjects ( Table 3, Supplemental Data set 1). Subjects with these ZIP12 variants have greater swMRI intensity across caudate, putamen, and pallidum.…”

Section: F I G U R Ementioning

confidence: 99%

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Role of zinc transporter ZIP12 in susceptibility‐weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function

et al. 2020

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Brain zinc dysregulation is linked to many neurological disorders. However, the mechanisms regulating brain zinc homeostasis are poorly understood. We performed secondary analyses of brain MRI GWAS and exome sequencing data from adults in the UK Biobank. Coding ZIP12 polymorphisms in zinc transporter ZIP12 (SLC39A12) were associated with altered brain susceptibility weighted MRI (swMRI). Conditional and joint association analyses revealed independent GWAS signals in linkage disequilibrium with 2 missense ZIP12 polymorphisms, rs10764176 and rs72778328, with reduced zinc transport activity. ZIP12 rare coding variants predicted to be deleterious were associated with similar impacts on brain swMRI. In Neuro‐2a cells, ZIP12 deficiency by short hairpin RNA (shRNA) depletion or CRISPR/Cas9 genome editing resulted in impaired mitochondrial function, increased superoxide presence, and detectable protein carbonylation. Inhibition of Complexes I and IV of the electron transport chain reduced neurite outgrowth in ZIP12 deficient cells. Transcriptional coactivator PGC‐1α, mitochondrial superoxide dismutase (SOD2), and chemical antioxidants α‐tocopherol, MitoTEMPO, and MitoQ restored neurite extension impaired by ZIP12 deficiency. Mutant forms of α‐synuclein and tau linked to familial Parkinson’s disease and frontotemporal dementia, respectively, reduced neurite outgrowth in cells deficient in ZIP12. Zinc and ZIP12 may confer resilience against neurological diseases or premature aging of the brain.

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Section: F I G U R Ementioning

confidence: 99%

“…performed by Cirulli et al56 included the total number of exome variants for SLC39A12 and individual…”

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confidence: 99%

Role of zinc transporter ZIP12 in susceptibility‐weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function

et al. 2020

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“…GWAS of protein traits have recently become viable [1][2][3][4][5][6] , but imputed GWAS chip data only offers partial insights into the genetic architecture of protein traits, in particular with respect to capturing rare variation. Large studies with proteomic data coupled to high-depth whole-genome sequencing, which is required to study the role of rare variation 7,8 , are currently lacking. Here, we perform whole-genome-sequence-based association analysis between 257 cardiometabolic disease-related serum protein levels 9 and 13,419,876 single nucleotide variants (SNVs) in a population-based cohort (MANOLIS), and assess colocalization, causation and predictive power of protein quantitative trait loci (pQTL) in cardiometabolic disease.…”

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confidence: 99%

Whole-genome sequencing analysis of the cardiometabolic proteome

et al. 2020

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The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we comprehensively assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance through high-depth (22.5×) whole-genome sequencing (WGS) in 1328 individuals. We discover 131 independent sequence variant associations (P < 7.45 × 10−11) across the allele frequency spectrum, all of which replicate in an independent cohort (n = 1605, 18.4x WGS). We identify for the first time replicating evidence for rare-variant cis-acting protein quantitative trait loci for five genes, involving both coding and noncoding variation. We construct and validate polygenic scores that explain up to 45% of protein level variation. We find causal links between protein levels and disease risk, identifying high-value biomarkers and drug development targets.

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“…In particular, individuals who share an IBD segment with a pathogenic rare variant carrier in a known gene have a higher probability of carrying the pathogenic variant (by inheriting it from the shared ancestor) than the general population, and would thus be at increased risk for the phenotypic effect. The UK Biobank exome pilot (45) identified multiple rare coding variant burden associations with complex phenotypes, some of which were recently replicated (48, 49). We set out to test whether our IBD inference could empower us to replicate and refine these associations using the larger non-sequenced cohort.…”

Section: Resultsmentioning

confidence: 99%

Identity-by-descent detection across 487,409 British samples reveals fine-scale population structure, evolutionary history, and trait associations

Saada

Kalantzis

Shyr

et al. 2020

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1Detection of Identical-By-Descent (IBD) segments provides a fundamental measure of genetic relatedness and plays a key 2 role in a wide range of genomic analyses. We developed a new method, called FastSMC, that enables accurate biobank-3 scale detection of IBD segments transmitted by common ancestors living up to several hundreds of generations in the past. 4 FastSMC combines a fast heuristic search for IBD segments with accurate coalescent-based likelihood calculations and enables 5 estimating the age of common ancestors transmitting IBD regions. We applied FastSMC to 487,409 phased samples from the 6 UK Biobank and detected the presence of ∼214 billion IBD segments transmitted by shared ancestors within the past 1, 500 7 years. We quantified time-dependent shared ancestry within and across 120 postcodes, obtaining a fine-grained picture of 8 genetic relatedness within the past two millennia in the UK. Sharing of common ancestors strongly correlates with geographic 9 distance, enabling the localization of a sample's birth coordinates from genomic data. We sought evidence of recent positive 10 selection by identifying loci with unusually strong shared ancestry within recent millennia and we detected 12 genome-wide 11 significant signals, including 7 novel loci. We found IBD sharing to be highly predictive of the sharing of ultra-rare variants in 12 exome sequencing samples from the UK Biobank. Focusing on loss-of-function variation discovered using exome sequencing, 13 we devised an IBD-based association test and detected 29 associations with 7 blood-related traits, 20 of which were not detected 14 in the exome sequencing study. These results underscore the importance of modelling distant relatedness to reveal subtle 15 population structure, recent evolutionary history, and rare pathogenic variation. 16 Introduction 17Large-scale genomic collection, through efforts like the NIH All of Us research program (1), the UK BioBank (2), and Ge-18 nomics England (3), has yielded datasets of hundreds of thousands of individuals and is expected to grow to millions in the 19 coming years. Utilizing such datasets to understand disease and health outcomes requires understanding the fine-scale genetic 20 relationships between individuals. These relationships can be characterized using short segments (less than 10 centimorgans 21[cM] in length) that are inherited identical by descent (IBD) from a common ancestor between purportedly "unrelated" pairs of 22 individuals in a dataset (4). Accurate detection of shared IBD segments has a number of downstream applications, which include 23 reconstructing the fine-scale demographic history of a population (5-8), detecting signatures of recent adaptation (9, 10), dis-24 covering phenotypic association (11, 12), estimating haplotype phase (4, 13, 14), and imputing missing genotype data (15, 16), 25 a key step in genome-wide association studies (GWAS) (17). Detection of IBD segments in millions of individuals within 26 modern biobanks poses a number of computational challenges. A...

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Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts

Cited by 127 publications

References 60 publications

Role of zinc transporter ZIP12 in susceptibility‐weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function

Role of zinc transporter ZIP12 in susceptibility‐weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function

Whole-genome sequencing analysis of the cardiometabolic proteome

Identity-by-descent detection across 487,409 British samples reveals fine-scale population structure, evolutionary history, and trait associations

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