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Large Copy-Number Variants in UK Biobank Caused by Clonal Hematopoiesis May Confound Penetrance Estimates

2020; Elsevier BV; Volume: 107; Issue: 2 Linguagem: Inglês

10.1016/j.ajhg.2020.06.001

ISSN

1537-6605

Autores

Marcus A. Tuke, Jessica Tyrrell, Katherine S. Ruth, Robin N. Beaumont, Andrew R. Wood, Anna Murray, Timothy M. Frayling, Michael N. Weedon, Caroline F. Wright,

Tópico(s)

Prenatal Screening and Diagnostics

Resumo

Large copy-number variants (CNVs) are strongly associated with both developmental delay and cancer, but the type of disease depends strongly on when and where the mutation occurred, i.e., germline versus somatic. We used microarray data from UK Biobank to investigate the prevalence and penetrance of large autosomal CNVs and chromosomal aneuploidies using a standard CNV detection algorithm not designed for detecting mosaic variants. We found 160 individuals that carry >10 Mb copy number changes, including 56 with whole chromosome aneuploidies. Nineteen (12%) individuals had a diagnosis of Down syndrome or other developmental disorder, while 84 (52.5%) individuals had a diagnosis of hematological malignancies or chronic myeloproliferative disorders. Notably, there was no evidence of mosaicism in the blood for many of these large CNVs, so they could easily be mistaken for germline alleles even when caused by somatic mutations. We therefore suggest that somatic mutations associated with blood cancers may result in false estimates of rare variant penetrance from population biobanks. Large copy-number variants (CNVs) are strongly associated with both developmental delay and cancer, but the type of disease depends strongly on when and where the mutation occurred, i.e., germline versus somatic. We used microarray data from UK Biobank to investigate the prevalence and penetrance of large autosomal CNVs and chromosomal aneuploidies using a standard CNV detection algorithm not designed for detecting mosaic variants. We found 160 individuals that carry >10 Mb copy number changes, including 56 with whole chromosome aneuploidies. Nineteen (12%) individuals had a diagnosis of Down syndrome or other developmental disorder, while 84 (52.5%) individuals had a diagnosis of hematological malignancies or chronic myeloproliferative disorders. Notably, there was no evidence of mosaicism in the blood for many of these large CNVs, so they could easily be mistaken for germline alleles even when caused by somatic mutations. We therefore suggest that somatic mutations associated with blood cancers may result in false estimates of rare variant penetrance from population biobanks. Copy number variants (CNVs) are deletions or duplications of DNA that can vary in size from 50 basepairs to several hundred megabases,1Zarrei M. MacDonald J.R. Merico D. Scherer S.W. A copy number variation map of the human genome.Nat. Rev. Genet. 2015; 16: 172-183Crossref PubMed Scopus (395) Google Scholar i.e., entire chromosomes. Individuals typically carry several thousand CNVs, most of which are small (<1 Mb) and rare (allele frequency < 1%).2Conrad D.F. Pinto D. Redon R. Feuk L. Gokcumen O. Zhang Y. Aerts J. Andrews T.D. Barnes C. Campbell P. et al.Wellcome Trust Case Control ConsortiumOrigins and functional impact of copy number variation in the human genome.Nature. 2010; 464: 704-712Crossref PubMed Scopus (1322) Google Scholar, 3Craddock N. Hurles M.E. Cardin N. Pearson R.D. Plagnol V. Robson S. Vukcevic D. Barnes C. Conrad D.F. Giannoulatou E. et al.Wellcome Trust Case Control ConsortiumGenome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.Nature. 2010; 464: 713-720Crossref PubMed Scopus (608) Google Scholar, 4Collins R.L. Brand H. Karczewski K.J. Zhao X. Alföldi J. Francioli L.C. Khera A.V. Lowther C. Gauthier L.D. Wang H. et al.Genome Aggregation Database Production TeamGenome Aggregation Database ConsortiumA structural variation reference for medical and population genetics.Nature. 2020; 581: 444-451Crossref PubMed Scopus (110) Google Scholar Large, rare pathogenic CNVs have historically been identified through clinical microarray testing of two distinct clinical cohorts: first, children with developmental disorders caused predominantly by germline mutations,5Cooper G.M. Coe B.P. Girirajan S. Rosenfeld J.A. Vu T.H. Baker C. Williams C. Stalker H. Hamid R. Hannig V. et al.A copy number variation morbidity map of developmental delay.Nat. Genet. 2011; 43: 838-846Crossref PubMed Scopus (846) Google Scholar, 6Coe B.P. Witherspoon K. Rosenfeld J.A. van Bon B.W.M. Vulto-van Silfhout A.T. Bosco P. Friend K.L. Baker C. Buono S. Vissers L.E.L.M. et al.Refining analyses of copy number variation identifies specific genes associated with developmental delay.Nat. 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Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy.Genome Biol. 2011; 12: R61Crossref PubMed Scopus (39) Google Scholar The availability of large, well-genotyped population biobanks offers an opportunity to investigate the prevalence and penetrance of monogenic disease-causing variants.11Wright C.F. West B. Tuke M. Jones S.E. Patel K. Laver T.W. Beaumont R.N. Tyrrell J. Wood A.R. Frayling T.M. et al.Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.Am. J. Hum. Genet. 2019; 104: 275-286Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Several studies have already been published evaluating known developmental CNVs in ∼500,000 adults in the UK and Estonian Biobanks12Crawford K. Bracher-Smith M. Owen D. Kendall K.M. Rees E. Pardiñas A.F. Einon M. Escott-Price V. Walters J.T.R. O'Donovan M.C. et al.Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank.J. Med. Genet. 2019; 56: 131-138Crossref PubMed Scopus (39) Google Scholar, 13Kendall K.M. Bracher-Smith M. Fitzpatrick H. Lynham A. Rees E. Escott-Price V. Owen M.J. O'Donovan M.C. Walters J.T.R. Kirov G. Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank.Br. J. Psychiatry. 2019; 214: 297-304Crossref PubMed Scopus (31) Google Scholar, 14Owen D. Bracher-Smith M. Kendall K.M. Rees E. Einon M. Escott-Price V. Owen M.J. O'Donovan M.C. Kirov G. Effects of pathogenic CNVs on physical traits in participants of the UK Biobank.BMC Genomics. 2018; 19: 867Crossref PubMed Scopus (16) Google Scholar, 15Kendall K.M. Rees E. Escott-Price V. Einon M. Thomas R. Hewitt J. O'Donovan M.C. Owen M.J. Walters J.T.R. Kirov G. Cognitive performance among carriers of pathogenic copy number variants: analysis of 152,000 UK biobank subjects.Biol. Psychiatry. 2017; 82: 103-110Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 16Kendall K.M. Rees E. Bracher-Smith M. Legge S. Riglin L. Zammit S. O'Donovan M.C. Owen M.J. Jones I. Kirov G. Walters J.T.R. Association of rare copy number variants with risk of depression.JAMA Psychiatry. 2019; 76: 818-825Crossref PubMed Scopus (24) Google Scholar, 17Macé A. Tuke M.A. Deelen P. Kristiansson K. Mattsson H. Nõukas M. Sapkota Y. Schick U. Porcu E. Rüeger S. et al.CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.Nat. Commun. 2017; 8: 744Crossref PubMed Scopus (29) Google Scholar, 18Männik K. Mägi R. Macé A. Cole B. Guyatt A.L. Shihab H.A. Maillard A.M. Alavere H. Kolk A. Reigo A. et al.Copy number variations and cognitive phenotypes in unselected populations.JAMA. 2015; 313: 2044-2054Crossref PubMed Scopus (88) Google Scholar, 19Aguirre M. Rivas M.A. Priest J. Phenome-wide Burden of Copy-Number Variation in the UK Biobank.Am. J. Hum. Genet. 2019; 105: 373-383Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar and the penetrance of X chromosome aneuploidy has been investigated in UK Biobank.20Tuke M.A. Ruth K.S. Wood A.R. Beaumont R.N. Tyrrell J. Jones S.E. Yaghootkar H. Turner C.L.S. Donohoe M.E. Brooke A.M. et al.Mosaic Turner syndrome shows reduced penetrance in an adult population study.Genet. Med. 2019; 21: 877-886Crossref PubMed Scopus (29) Google Scholar However, given the relatively advanced age of UK Biobank participants, ranging from 40 to 70 years (mean = 56.5 years) at recruitment, it is likely that some variants will be due to somatic mutation and age-related clonal hematopoiesis21Genovese G. Kähler A.K. Handsaker R.E. Lindberg J. Rose S.A. Bakhoum S.F. Chambert K. Mick E. Neale B.M. Fromer M. et al.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N. Engl. J. Med. 2014; 371: 2477-2487Crossref PubMed Scopus (1539) Google Scholar,22Jaiswal S. Ebert B.L. Clonal hematopoiesis in human aging and disease.Science. 2019; 366: 366Crossref Scopus (153) Google Scholar as has previously been observed in genome-wide association study cohorts.23Vattathil S. Scheet P. Extensive hidden genomic mosaicism revealed in normal tissue.Am. J. Hum. Genet. 2016; 98: 571-578Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar,24Machiela M.J. Zhou W. Sampson J.N. Dean M.C. Jacobs K.B. Black A. Brinton L.A. Chang I.-S. Chen C. Chen C. et al.Characterization of large structural genetic mosaicism in human autosomes.Am. J. Hum. Genet. 2015; 96: 487-497Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Importantly, somatic variants in adult population cohorts should not be used to evaluate the penetrance of germline CNVs known to cause developmental disorders, as this will result in spurious associations. We sought to investigate large (>10 Mb) autosomal CNVs present in population datasets with the aim of determining whether they were likely to be germline (and therefore potentially useful for penetrance studies) or somatic (and therefore caused by clonal expansions). We used microarray data from UK Biobank, which recruited 502,506 individuals from across the UK between 2006 and 2010.25Bycroft C. Freeman C. Petkova D. Band G. Elliott L.T. Sharp K. Motyer A. Vukcevic D. Delaneau O. O'Connell J. et al.The UK Biobank resource with deep phenotyping and genomic data.Nature. 2018; 562: 203-209Crossref PubMed Scopus (1148) Google Scholar Hospital Episode Statistics (HES) and cancer registry data were available for the whole cohort up to 31 March 2017, and GP records were available for half the cohort; all participants also provided a range of information (e.g., demographics, health status, lifestyle) via questionnaires. Genotypes for SNVs and indels were generated from blood-extracted DNA using the Affymetrix Axiom UK Biobank array (∼450,000 individuals) and the UKBiLEVE array (∼50,000 individuals) in 106 batches of ∼4,700 samples. This dataset underwent extensive central quality control.25Bycroft C. Freeman C. Petkova D. Band G. Elliott L.T. Sharp K. Motyer A. Vukcevic D. Delaneau O. O'Connell J. et al.The UK Biobank resource with deep phenotyping and genomic data.Nature. 2018; 562: 203-209Crossref PubMed Scopus (1148) Google Scholar We called CNVs genome-wide in 488,377 individuals with array genotyping data in UK Biobank25Bycroft C. Freeman C. Petkova D. Band G. Elliott L.T. Sharp K. Motyer A. Vukcevic D. Delaneau O. O'Connell J. et al.The UK Biobank resource with deep phenotyping and genomic data.Nature. 2018; 562: 203-209Crossref PubMed Scopus (1148) Google Scholar using PennCNV version 1.0.426Wang K. Li M. Hadley D. Liu R. Glessner J. Grant S.F.A. Hakonarson H. Bucan M. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data.Genome Res. 2007; 17: 1665-1674Crossref PubMed Scopus (1180) Google Scholar with log R ratio and B-allele frequency values for 805,426 genome-wide probe sets provided by UK Biobank. Very large PennCNV calls (i.e., multiple megabases) can sometimes be fragmented into many smaller calls, so we additionally calculated the sum of bases either deleted or duplicated on each chromosome per individual according to the PennCNV calls. We carried out visual inspection of each event in everyone with >10 Mb deleted and/or duplicated on a single chromosome to confirm breakpoints, event type and level of mosaicism (see examples in Figure 1). Around a third of the events showed no evidence of mosaicism in blood (based on a deviation of the B-allele frequencies from 0, 0.5, or 1 with a co-located increase/decrease in log R ratio) while two-thirds of events were consistent with the presence of a large CNV in a proportion of cells. Based on previous work investigating mosaicism in UK Biobank,20Tuke M.A. Ruth K.S. Wood A.R. Beaumont R.N. Tyrrell J. Jones S.E. Yaghootkar H. Turner C.L.S. Donohoe M.E. Brooke A.M. et al.Mosaic Turner syndrome shows reduced penetrance in an adult population study.Genet. Med. 2019; 21: 877-886Crossref PubMed Scopus (29) Google Scholar,27Loh P.-R. Genovese G. Handsaker R.E. Finucane H.K. Reshef Y.A. Palamara P.F. Birmann B.M. Talkowski M.E. Bakhoum S.F. McCarroll S.A. Price A.L. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations.Nature. 2018; 559: 350-355Crossref PubMed Scopus (94) Google Scholar we estimate that we were able to detect copy number changes present in >20%–25% of cells. There was a good correlation between the log R ratio and visual inspection of mosaicism28Conlin L.K. Thiel B.D. Bonnemann C.G. Medne L. Ernst L.M. Zackai E.H. Deardorff M.A. Krantz I.D. Hakonarson H. Spinner N.B. Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis.Hum. Mol. Genet. 2010; 19: 1263-1275Crossref PubMed Scopus (293) Google Scholar (Figure 2).Figure 2Mean Log R Ratio of CNVsShow full captionBoxplot of mean log R ratios of large CNVs, grouped by whether there was evidence of mosaicism based on visual inspection of the data. Red, deletion (DEL); blue, duplication (DUP); green, triplication (TRIP); median and interquartile ranges shown.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Boxplot of mean log R ratios of large CNVs, grouped by whether there was evidence of mosaicism based on visual inspection of the data. Red, deletion (DEL); blue, duplication (DUP); green, triplication (TRIP); median and interquartile ranges shown. We identified 160 individuals in UK Biobank (61% male versus 46% in the whole of UK Biobank; Pearson's chi-square p = 0.025) with >10 Mb involved in copy number events on a single autosome (Figure 3 and Table S1). This male bias has been observed previously and is thought to be due to higher male-specific rates of certain hematological malignancies.24Machiela M.J. Zhou W. Sampson J.N. Dean M.C. Jacobs K.B. Black A. Brinton L.A. Chang I.-S. Chen C. Chen C. et al.Characterization of large structural genetic mosaicism in human autosomes.Am. J. Hum. Genet. 2015; 96: 487-497Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar In the majority (134/160) of individuals, this was caused by a single large CNV; 19 individuals had 2 separate events (17 on 2 different chromosomes); 5 individuals had 3 separate events (all involving at least 2 different chromosomes); and 2 individuals had 4 or 5 separate events on the same chromosome. Individual events ranged in size from 0.9 Mb to 198 Mb (mean = 56 Mb, stdev = 51 Mb) and included both unique events and recurrent events. There were 64 whole chromosome duplications of chromosomes 3, 8, 9, 12, 14, 18, 19, and 21, including four individuals with two trisomies and three individuals with three trisomies. Of the autosomal aneuploidies, only trisomy 21 is compatible with adult life when present constitutively and causes Down syndrome.29Hassold T. Hunt P. To err (meiotically) is human: the genesis of human aneuploidy.Nat. Rev. Genet. 2001; 2: 280-291Crossref PubMed Scopus (1618) Google Scholar Twelve individuals had a duplication of chromosome 21, of whom 11 had a diagnosis of Down syndrome in their HES or GP records (GP records were not available for the remaining individual). A further six individuals in UK Biobank had Down syndrome recorded in their HES records, but their microarray data showed no evidence of trisomy 21. It is unclear whether these discrepancies are caused by sample mix-ups, errors in HES records, or misdiagnoses. Of those with large CNVs, a further eight individuals had ICD-10 codes or GP records consistent with various developmental disorders, including congenital malformations, developmental disorder (intellectual disability/handicap or epilepsy), and bipolar affective disorder (Table S1). We suggest that the rest of the whole chromosome duplications and the majority of large CNVs are likely to be somatic mutations caused by clonal expansions, some of which are compatible with being present in (apparently) healthy individuals. Several lines of evidence suggest that the majority of the large CNVs were likely caused by somatic mutations associated with either cancer10Ozery-Flato M. Linhart C. Trakhtenbrot L. Izraeli S. Shamir R. Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy.Genome Biol. 2011; 12: R61Crossref PubMed Scopus (39) Google Scholar,30Ben-David U. Amon A. Context is everything: aneuploidy in cancer.Nat. Rev. Genet. 2020; 21: 44-62Crossref PubMed Scopus (83) Google Scholar or age-related hematopoietic clonal expansions.22Jaiswal S. Ebert B.L. Clonal hematopoiesis in human aging and disease.Science. 2019; 366: 366Crossref Scopus (153) Google Scholar,31Shlush L.I. Age-related clonal hematopoiesis.Blood. 2018; 131: 496-504Crossref PubMed Scopus (117) Google Scholar First, 79/160 (50%) individuals had a recurrent duplication of chromosome 8, 9, 12, or 19 or large deletions on chromosome 11q, 13q, 17p, and 20q that are consistent with those observed previously in lymphocytic and myeloid leukemias10Ozery-Flato M. Linhart C. Trakhtenbrot L. Izraeli S. Shamir R. Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy.Genome Biol. 2011; 12: R61Crossref PubMed Scopus (39) Google Scholar,30Ben-David U. Amon A. Context is everything: aneuploidy in cancer.Nat. Rev. Genet. 2020; 21: 44-62Crossref PubMed Scopus (83) Google Scholar,32Landau D.A. Tausch E. Taylor-Weiner A.N. Stewart C. Reiter J.G. Bahlo J. Kluth S. Bozic I. Lawrence M. Böttcher S. et al.Mutations driving CLL and their evolution in progression and relapse.Nature. 2015; 526: 525-530Crossref PubMed Scopus (571) Google Scholar,33Marasca R. Maffei R. Martinelli S. Fiorcari S. Bulgarelli J. Debbia G. Rossi D. Rossi F.M. Rigolin G.M. Martinelli S. et al.Clinical heterogeneity of de novo 11q deletion chronic lymphocytic leukaemia: prognostic relevance of extent of 11q deleted nuclei inside leukemic clone.Hematol. Oncol. 2013; 31: 88-95Crossref PubMed Scopus (23) Google Scholar and JAK2-related myeloproliferative neoplasms.34James C. Ugo V. Le Couédic J.-P. Staerk J. Delhommeau F. Lacout C. Garçon L. Raslova H. Berger R. Bennaceur-Griscelli A. et al.A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2715) Google Scholar Second, 98/160 (61%) individuals had neoplasms recorded in their HES records or cancer registry data compared with 80,046 (17%) across the whole of UK Biobank (p < 2 × 10−16). Sixty-four (40%) were malignant neoplasms of lymphoid, hematopoietic, and related tissues (ICD-10 codes: C81-96), a significant enrichment above the whole of UK Biobank (n = 3,869, 0.8%, p < 2 × 10−16); and a further 20 were polycythemia vera, myelodysplastic syndrome, and chronic myeloproliferative diseases (ICD-10 codes: D45-47), again a significant enrichment above the whole of UK Biobank (n = 646, 0.1% p < 2 × 10−16). Third, individuals with large CNVs and neoplasms were older and taller versus the others with large CNVs but no record of neoplasms, as expected in cancer; in contrast, individuals with large CNVs and a developmental disorder were younger and shorter versus the others, consistent with many developmental disorders (Figure 4). Nonetheless, 43/160 (27%) individuals with a large CNV in UK Biobank have neither a developmental disorder nor a neoplasm (of any sort) recorded to date. This observation has a range of explanations, including record error, lack of hospitalization, absence of GP records (currently available for only around half the cohort), benign hematopoietic clonal expansions, or neoplasms that have not yet developed or been diagnosed. Given the prognostic link between chromosomal instability and tumorigenesis,30Ben-David U. Amon A. Context is everything: aneuploidy in cancer.Nat. Rev. Genet. 2020; 21: 44-62Crossref PubMed Scopus (83) Google Scholar,35Danielsen H.E. Pradhan M. Novelli M. Revisiting tumour aneuploidy - the place of ploidy assessment in the molecular era.Nat. Rev. Clin. Oncol. 2016; 13: 291-304Crossref PubMed Scopus (80) Google Scholar unfortunately the latter explanation is likely to be true in many cases. Mosaic chromosomal alterations27Loh P.-R. Genovese G. Handsaker R.E. Finucane H.K. Reshef Y.A. Palamara P.F. Birmann B.M. Talkowski M.E. Bakhoum S.F. McCarroll S.A. Price A.L. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations.Nature. 2018; 559: 350-355Crossref PubMed Scopus (94) Google Scholar and Y chromosome loss36Thompson D.J. Genovese G. Halvardson J. Ulirsch J.C. Wright D.J. Terao C. Davidsson O.B. Day F.R. Sulem P. Jiang Y. et al.International Lung Cancer Consortium (INTEGRAL-ILCCO)Breast Cancer Association ConsortiumConsortium of Investigators of Modifiers of BRCA1/2Endometrial Cancer Association ConsortiumOvarian Cancer Association ConsortiumProstate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) ConsortiumKidney Cancer GWAS Meta-Analysis ProjecteQTLGen ConsortiumBiobank-based Integrative Omics Study (BIOS) Consortium23andMe Research TeamGenetic predisposition to mosaic Y chromosome loss in blood.Nature. 2019; 575: 652-657Crossref PubMed Scopus (52) Google Scholar in UK Biobank have previously been linked to age-related clonal hematopoiesis, both of which can be easily excluded from studies seeking to investigate penetrance of germline CNVs. Indeed, although some mosaic variants can be detected by PennCNV, low-level mosaic variants are often not detected using standard variant calling algorithms. However, the presence of very rare autosomal aneuploidies, some of which do not appear to be mosaic based on intensity data from microarrays, suggest that caution should be used when interpreting rare variants (of any size) in population biobanks. For example, we note that six individuals in UK Biobank have complete or partial trisomy of chromosome 3, of whom 5/6 have non-Hodgkin's lymphoma. Presumed germline duplications of 3q29 have previously been causally linked with early death (OR = 27.8) and cancer (OR = 37.5) in UK Biobank,12Crawford K. Bracher-Smith M. Owen D. Kendall K.M. Rees E. Pardiñas A.F. Einon M. Escott-Price V. Walters J.T.R. O'Donovan M.C. et al.Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank.J. Med. Genet. 2019; 56: 131-138Crossref PubMed Scopus (39) Google Scholar but we suggest that these associations more likely reflect reverse causality, with cancer causing chromosome 3 duplication and early death. A similar issue has previously been highlighted for sequence variants in cancer driver genes where rare mutations are also a cause of developmental disorders, such as ASXL1 and DNMT3A.37Carlston C.M. O'Donnell-Luria A.H. Underhill H.R. Cummings B.B. Weisburd B. Minikel E.V. Birnbaum D.P. Tvrdik T. MacArthur D.G. Mao R. Exome Aggregation ConsortiumPathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome.Hum. Mutat. 2017; 38: 517-523Crossref PubMed Scopus (24) Google Scholar Based on our analysis, the issue of somatic mutations confounding analyses of variants presumed to be germline can only be partially addressed by assigning the mosaic status of each variant; critically evaluating the validity of a variant (such as the breakpoints of a CNV), the plausibility of a finding (such as presence of constitutive autosomal aneuploidy), and likelihood of different mutational mechanisms (such as clonal expansion) are also important. As genome-wide sequencing becomes widely available in aging cohorts such as UK Biobank, researchers should be aware of potential confounding caused by somatic mutations present in high proportions of cells. This research has been conducted using the UK Biobank Resource under Application Number 49847. The authors would like to acknowledge the use of the University of Exeter High-Performance Computing facility in carrying out this work. The authors declare no competing interests. This study did not generate new datasets or code. The code used during this study is available at https://github.com/WGLab/PennCNV. All bona fide researchers can apply to use the UK Biobank resource for health-related research that is in the public interest, https://www.ukbiobank.ac.uk/. Download .xlsx (.03 MB) Help with xlsx files Table S1List of All >10 Mb Copy Number Changes in UK Biobank Detected via SNP-Genotyping Arrays DUP, duplication; DEL, deletion; LRR, log R ratio; St Dev LRR, standard deviation of the log R ratio; N SNPs, number of SNPs in the call.

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