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Cited by 697Genetic Associations and EpidemiologyGenomics and Rare DiseasesGenetic Mapping and Diversity in Plants and Animals

A brief history of human disease genetics

Open access
Claussnitzer, Melina, Cho, Judy H., Collins, Rory, Cox, Nancy J., Dermitzakis, Emmanouil T., Hurles, Matthew E., Kathiresan, Sekar, Kenny, Eimear E. +10 more·2020·Nature
DOI 10.1038/s41586-019-1879-7PMC PMC7405896
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Abstract

A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition. This Review describes progress in the study of human genetics, in which rapid advances in technology, foundational genomic resources and analytical tools have contributed to the understanding of the mechanisms responsible for many rare and common diseases and to preventative and therapeutic strategies for many of these conditions.

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Claims the paper makes

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  • Interpretationreasoning

    The long-standing division between genetic discovery for rare large-effect variants and common disease predisposition alleles has obscured the continuous spectrum of disease risk alleles across frequencies and effect sizes observed in populations.

    “We describe how this division, with its echoes of the century-old debate between Mendelian and biometric views of human genetics, has obscured the continuous spectrum of disease risk alleles–across the range of frequencies and effect sizes–observed in the population”
    Quote in the paperSubstantial claim
  • Premisecitation

    Interactions between researchers and families with rare disease have enabled natural history studies driven by family support groups that initiate data collection once a causal gene is discovered.

    “Interactions between researchers and families with rare disease have enabled natural history studies to be driven by family support groups positioned to initiate data collection from patient cohorts once a causal gene is discovered20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Kennedy, J. et al. KAT6A syndrome: genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants. Genet. Med. 21, 850–860 (2019). source

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  • Premisecitation

    Microarray-based detection of structural variation and exome- and genome-wide sequencing have been pivotal for rare disease gene discovery, supported by in silico analysis and variant prioritization.

    “Microarray-based detection of structural variation10 and exome-and genome-wide sequencing11,12 have been pivotal, bolstered by in silico analysis and prioritization of the discovered genetic variants.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Vissers, L. E. et al. Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. Am. J. Hum. Genet. 73, 1261–1270 (2003). source

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    • cites [11] Ng, S. B. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009). source

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    • cites [12] Wheeler, D. A. et al. The complete genome of an individual by massively parallel DNA sequencing. Nature 452, 872–876 (2008). source

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  • Premisereasoning

    Recognition that this haplotype configuration could support genome-wide surveys of association energized technological innovation in massively parallel genotyping arrays.

    “Recognition that this configuration could support genome-wide surveys of association energized the technological innovation–in the form of massively parallel genotyping arrays–to make such studies possible (Fig. 1).”
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  • Premisecitation

    Reduced reliance on multiplex pedigrees in favour of collections of affected cases, often with parents, has been decisive in identifying new dominant disorders, many previously considered recessive.

    “Reduced reliance on multiplex pedigrees in favour of collections of affected cases, often with parents13, has proven decisive in identifying new dominant disorders, many of which were previously considered recessive14.”
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    • cites [13] Vissers, L. E. et al. A de novo paradigm for mental retardation. Nat. Genet. 42, 1109–1112 (2010). source

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    • cites [14] Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 542, 433–438 (2017). source

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  • Classified as probably not a substantial claim. 21
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    Interpretationnone given

    Genome-wide analyses in large biobanks are transforming genetic research by enabling a comprehensive perspective on genotype-phenotype relationships.

    “outline how genome-wide analyses in large biobanks are transforming genetic research by enabling a comprehensive perspective on genotype–phenotype relationships”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Over the past 25 years, progress in identifying DNA variants that influence disease has been transformed by advances in technology, foundational genomic resources, analytical tools, and access to large genotype and phenotype datasets.

    “Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Characterizing the relationship between sequence variation and disease predisposition provides a powerful tool for identifying processes fundamental to disease pathogenesis and highlighting novel prevention and treatment strategies.

    “Consequently, characterizing the relationship between sequence variation and disease predisposition provides a powerful tool for identifying processes fundamental to disease pathogenesis and highlighting novel strategies for prevention and treatment.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: For almost all human diseases, individual susceptibility is influenced to some degree by genetic variation.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Genetic discoveries have substantially improved understanding of mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies.

    “Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies.”
    Quote in the paperNot a substantial claim

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    Interpretationnone given

    Knowledge from human genetics increasingly underpins advances in clinical care.

    “and the ways in which this knowledge increasingly underpins advances in clinical care”
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    Premisecitation

    By 2000, around 1,000 of the estimated 7,000 single-gene inherited diseases had been characterized, including Huntington's disease and cystic fibrosis.

    “by 2000, around 1,000 of the estimated 7,000 single-gene inherited diseases had been characterized, including many with substantial biomedical impact, such as Huntington’s disease and cystic fibrosis7–9.”
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    • cites [7] Kremer, B. et al. A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats. N. Engl. J. Med. 330, 1401–1406 (1994). source

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    • cites [8] Collins, F. S. Identifying human disease genes by positional cloning. Harvey Lect. 86, 149–164 (1990–1991).

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    • cites [9] Gusella, J. F. & MacDonald, M. E. Huntington’s disease and repeating trinucleotides. N. Engl. J. Med. 330, 1450–1451 (1994). source

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    Premisecitation

    Completion of the draft human genome sequence reduced obstacles to disease-gene mapping and propelled a fourfold increase in genes implicated as causal for rare single-gene disorders.

    “Completion of the draft human genome sequence1 reduced many of the obstacles to disease-gene mapping and propelled a fourfold increase in the genes implicated as causal for rare, single-gene disorders (Fig. 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001). This paper describes the first analyses from the draft human genome sequence assembled over the previous decade: it launched modern human genetics and represents a tribute to the power of collaborative science. source

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    Premisenone given

    Initial candidate-gene association efforts were plagued by inadequate power, liberal significance thresholds, and scant attention to bias and confounding, resulting in overblown claims and failed replication.

    “However, initial efforts targeting variants within ‘candidate’ genes were plagued by inadequate power, unduly liberal thresholds for declaring significance and scant attention to sources of bias and confounding, resulting in overblown claims and failed replication.”
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    Interpretationnone given

    Expansion in scale and scope of strategies for enumerating functional consequences of genetic variation is transforming genetic discoveries from the past decade into mechanistic insights.

    “We describe how the expansion in the scale and scope of strategies for enumerating the functional consequences of genetic variation is transforming the torrent of genetic discoveries from the past decade into mechanistic insights”
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    Premisenone given

    During the 1980s and 1990s, efforts to map disease genes focused on rare, monogenic and syndromic diseases and were mostly driven by linkage analysis and fine mapping within large multiplex pedigrees.

    “During the 1980s and 1990s, efforts to map disease genes were focused on rare, monogenic and syndromic diseases and were mostly driven by linkage analysis and fine mapping within large multiplex pedigrees.”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning

    These sequencing technologies have extended from research into clinical usage, driving earlier and faster diagnosis for genetic disorders.

    “These technologies have extended from research into clinical usage, driving earlier and faster diagnosis for genetic disorders.”
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    Interpretationcitation

    These analyses have reduced contamination of databases with variants erroneously interpreted as causal and are addressing overestimation of disease penetrance arising from historical focus on multiplex pedigrees.

    “These analyses have reduced the contamination of databases with variants erroneously interpreted as causal for disease, and are addressing the overestimation of disease penetrance arising from the historical focus on multiplex pedigrees25.”
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    • cites [25] Flannick, J. et al. Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Nat. Genet. 45, 1380–1385 (2013). source

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    Premisecitation

    Establishing the causal role of individual variants within genes associated with rare disorders remains problematic, and many patients with suspected rare genetic diseases lack a definitive diagnosis.

    “Although huge strides have been made in associating specific genes with particular disorders, establishing the causal role of individual variants within those genes remains problematic, and many patients with suspected rare genetic diseases are left without a definitive diagnosis28.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] MacArthur, D. G. et al. Guidelines for investigating causality of sequence variants in human disease. Nature 508, 469–476 (2014). source

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    Premisenone given

    Most variants uncovered by early GWAS were common and had more subtle effects than many had anticipated.

    “Most variants uncovered by these early genome-wide association studies (GWAS) were common, with more subtle effects than many had anticipated.”
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    Interpretationreasoning

    Systematic data sharing has been critical for characterizing new disorders and for diagnostic interpretation of potential causal alleles.

    “A more systematic approach to data sharing has been critical, both for the characterization of new disorders and diagnostic interpretation of potential causal alleles.”
    Quote in the paperSubstantial claim

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    Premisecitation

    GWAS signals have revealed unexpected insights into biological basis of complex disease, including complement in acute macular degeneration, synaptic pruning in schizophrenia, and autophagy in inflammatory bowel disease.

    “Examples include the role of complement in the pathogenesis of acute macular degeneration38, synaptic pruning in schizophrenia64 and autophagy in inflammatory bowel disease65.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [38] Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005). Arguably the first full GWAS, this study demonstrated the potential of agnostic genomic surveys to highlight entirely novel biology—in this case, a role for complement in the pathogenesis of macular degeneration. source

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    • cites [64] Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016). source

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    • cites [65] Jostins, L. et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012). source

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    Interpretationcitation

    Because inherited sequence variation is a prominent cause of phenotypic variation (but the reverse is not true), risk variants identified by GWAS have value as genetic instruments for mapping causal relationships between traits and inferring contributions of biomarkers and environmental exposures to disease.

    “In addition, as inherited sequence variation is a prominent cause of phenotypic variation (but the reverse is not true), risk variants identified by GWAS have value as genetic instruments, mapping causal relationships between traits and inferring contributions made by circulating biomarkers and environmental exposures to disease development66.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Richardson, T. G., Harrison, S., Hemani, G. & Davey Smith, G. An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome. eLife 8, e43657 (2019). source

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    • Rests on an assumption: Inherited sequence variation is a prominent cause of phenotypic variation, while phenotypic variation does not cause inherited sequence variation.

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    Premisenone given

    Extensive linkage disequilibrium within human populations has been essential to GWAS discovery, but high correlation between adjacent variants frustrates mapping of specific causal variants.

    “While the extensive linkage disequilibrium within human populations has been essential to discovery in GWAS, high correlation between adjacent variants frustrates mapping of the specific variants responsible for these associations.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Studies in populations with high rates of consanguinity make it possible to identify individuals homozygous for otherwise rare loss-of-function alleles, forming the basis for a human knockout project.

    “In addition, studies in populations with high rates of consanguinity make it possible to identify individuals homozygous for otherwise rare loss-of-function alleles, the basis for a ‘human knockout’ project to systematically investigate the phenotypic consequences of gene disruption in humans53,54.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Narasimhan, V. M. et al. Health and population effects of rare gene knockouts in adult humans with related parents. Science 352, 474–477 (2016). A powerful illustration of the insights that can be gained from the study of individuals who are homozygous carriers of null alleles in genes of biomedical interest. source

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    • cites [54] Saleheen, D. et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature 544, 235–239 (2017). source

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    Premisecitation

    UK Biobank, including 500,000 largely healthy middle-aged participants, has been particularly influential and transformed human genetic research partly through permissive data-sharing policies.

    “The UK Biobank study, including 500,000 largely healthy, middle-aged participants has been particularly influential, transforming human genetic research in part through permissive data-sharing policies that have allowed multiple research groups to analyse the data74.”
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    • cites [74] Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018). source

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    Interpretationcitation

    Common diseases are not simply aggregations of related Mendelian conditions; for most complex traits, genetic predisposition is shared across thousands of mostly common variants with individually modest effects on population risk.

    “Common diseases are not simply aggregations of related Mendelian conditions: for most complex traits, genetic predisposition is shared across thousands of mostly common variants with individually modest effects on population risk41,43.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Mahajan, A. et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat. Genet. 50, 1505–1513 (2018). source

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    • cites [43] Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010). source

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    Interpretationcitation

    GWAS findings have increasing translational impact through identification of novel therapeutic targets, prioritization and deprioritization of existing targets, and development of polygenic scores that quantify individual genetic risk.

    “As described below, findings from GWAS have increasing translational impact through identification of novel therapeutic targets67, prioritization (and deprioritization) of existing ones68 and development of polygenic scores that quantify individual genetic risk69.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [67] Dendrou, C. A. et al. Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity. Sci. Transl. Med. 8, 363ra149 (2016). source

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    • cites [68] Voight, B. F. et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 380, 572–580 (2012). source

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    • cites [69] Khera, A. V. et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat. Genet. 50, 1219–1224 (2018). This paper used large-scale genetic data to demonstrate the clinical potential of the polygenic scores that can be constructed for many common diseases, emphasizing that, in some situations, the lifetime risk of disease for those with the highest scores approaches that of established monogenic disease. source

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    Premisecitation

    For many traits, there is clear convergence between common-variant association signals and genes implicated in monogenic forms of the same disease, as well as enrichment of GWAS signals in regulatory elements active in cell types consistent with known disease biology.

    “For many traits, there is clear convergence between common-variant association signals and genes implicated in monogenic forms of the same disease, as well as enrichment of GWAS signals in regulatory elements specifically active in cell types consistent with known disease biology60,61.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Farh, K. K. et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015). An early demonstration of the value of overlapping genome-wide association data with tissue-specific regulatory maps to define the cell-types and tissues likely to be driving disease pathology. source

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    • cites [61] Freund, M. K. et al. Phenotype-specific enrichment of Mendelian disorder genes near GWAS regions across 62 complex traits. Am. J. Hum. Genet. 103, 535–552 (2018). source

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    Interpretationnone given

    Rare risk alleles detected in current sample sizes necessarily have large phenotypic effects and are proportionately more likely to be coding, enhancing their value for biological inference.

    “the rare risk alleles detected in current sample sizes necessarily have large phenotypic effects and are proportionately more likely to be coding, enhancing their value for biological inference.”
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    Premisecitation

    GTEx has mapped thousands of expression quantitative trait loci across hundreds of individuals and dozens of tissues.

    “For example, the GTEx (Genotype-Tissue Expression) consortium has mapped thou sands of expression quantitative trait loci (QTLs) across hundreds of individuals and dozens of tissues112.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] GTEx Consortium. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017). One of several papers describing the results obtained from the Genotype-Tissue Expression (GTEx) project, which used RNA-sequence data from more than 40 human tissues in several hundred individuals to explore the relationship between DNA sequence variation and tissue-specific expression. source

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  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Success in this endeavour depends on ever greater harmonization between, and integration of results from, individual studies through sustained investments in data sharing.

    “Success in this endeavour depends on ever greater harmonization between, and integration of results from, individual studies through sustained investments in data sharing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    For common diseases, functional studies have a more fundamental role.

    “For common diseases, functional studies have a more fundamental role.”
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    Premisecitation

    Pervasive pleiotropy complicates interpretation: many variants identified by GWAS are associated with multiple traits and exert diverse effects across multiple cell types.

    “Growing appreciation of the pervasive role of pleiotropy complicates matters: many variants identified by GWAS are associated with multiple traits and exert diverse effects across multiple cell types100.”
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    • cites [100] Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015). source

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    Interpretationcitation

    Patterns of genomic overlap between these functional data and GWAS results enable functional inference of risk variants, deliver clues to specific cell types driving disease pathogenesis, and accelerate locus-specific mechanistic insights.

    “The patterns of genomic overlap between these data and GWAS results enable the functional inference of risk variants, deliver clues to the specific cell types driving disease pathogenesis60,109 and accelerate locus-specific mechanistic insights.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] Farh, K. K. et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015). An early demonstration of the value of overlapping genome-wide association data with tissue-specific regulatory maps to define the cell-types and tissues likely to be driving disease pathology. source

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    • cites [109] Tansey, K. E., Cameron, D. & Hill, M. J. Genetic risk for Alzheimer’s disease is concentrated in specific macrophage and microglial transcriptional networks. Genome Med. 10, 14 (2018). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Progress in determining how variants influence disease through systematic interrogation of their functional effects has been far slower than progress in mapping genetic factors.

    “However, progress in determining how these variants influence disease, through systematic interrogation of their functional effects on molecular, cellular and physiological processes, has been far slower.”
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    Interpretationcitation

    These findings inform prioritization of therapeutic targets, providing clues to potential on-target side effects and opportunities for drug repurposing.

    “These findings inform the prioritization of therapeutic targets, providing clues to potential on-target side effects and opportunities for drug repurposing87–89.”
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    • cites [87] Gudmundsson, J. et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat. Genet. 39, 977–983 (2007). source

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    • cites [88] Abul-Husn, N. S. et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N. Engl. J. Med. 378, 1096–1106 (2018). source

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    • cites [89] Plenge, R. M., Scolnick, E. M. & Altshuler, D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013). source

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    Most direct analysis of high-throughput sequence data has focused on coding regions.

    “Most direct analysis of high-throughput sequence data has focused on the coding regions.”
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    Interpretationcitation

    This enables more rigorous evaluation of the contribution of rare and common variants to trait susceptibility and supports enumeration of allelic series critical for studies of disease mechanism and therapeutic target optimization.

    “This enables more rigorous evaluation of the contribution of rare and common variants to trait susceptibility48 and supports the enumeration of ‘allelic series’ (sets of alleles of varying frequency, effect size and direction that disrupt the same gene) critical for studies of disease mechanism and therapeutic target optimization89,96.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [48] Wainschtein, P. et al. Recovery of trait heritability from whole genome sequence data. Preprint at bioRxiv https://doi.org/10.1101/588020 (2019). source

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    • cites [89] Plenge, R. M., Scolnick, E. M. & Altshuler, D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013). source

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    • cites [96] Rivas, M. A. et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat. Genet. 43, 1066–1073 (2011). source

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    Premisecitation

    These developments have enabled researchers to bridge the gap between monogenic and polygenic realms, identifying common variant modifiers of monogenic phenotypes and low-frequency and rare variants influencing common multifactorial traits.

    “These developments have enabled researchers to bridge the gap between the monogenic and polygenic realms, identifying common variant modifiers of monogenic phenotypes contributing to the variable expression of rare, large-effect alleles26,93, and low-frequency and rare variants that influence common multifactorial traits94,95.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [26] Bečanović, K. et al. A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease. Nat. Neurosci. 18, 807–816 (2015). source

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    • cites [93] Khera, A. V. et al. Whole-genome sequencing to characterize monogenic and polygenic contributions in patients hospitalized with early-onset myocardial infarction. Circulation 139, 1593–1602 (2019). source

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    • cites [94] Grarup, N. et al. Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes. Nat. Genet. 50, 172–174 (2018). source

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    • cites [95] Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006). source

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    Premisecitation

    Although tens of thousands of associations have been discovered across common human diseases and traits, multiple factors have frustrated efforts to convert genetic signals to knowledge about causal variants, genes and mechanisms.

    “Although tens of thousands of associations have been discovered across thousands of common human diseases and traits44, multiple factors have frustrated efforts to convert these genetic signals to knowledge about causal variants, genes and mechanisms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Buniello, A. et al. The NHGRI–EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 47, D1005–D1012 (2019). source

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    Premisecitation

    Unlike common diseases, the clarity of causation for Mendelian disorders usually simplifies generating models to connect genotype to organismal phenotype, and these models have led to critical insights into human health and disease biology.

    “Unlike common diseases, the clarity of causation for Mendelian disorders usually simplifies the task of generating models (including human cells and organoids or rodents) to connect genotype to organismal phenotype; these have led to many critical insights into the biology of health and disease in humans98,99.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [98] Goldstein, J. L. & Brown, M. S. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161, 161–172 (2015). source

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    • cites [99] Peltonen, L., Perola, M., Naukkarinen, J. & Palotie, A. Lessons from studying monogenic disease for common disease. Hum. Mol. Genet. 15, R67–R74 (2006). source

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    Premisenone given

    Most GWAS associations map to the noncoding genome and thus lack a direct address to the gene that mediates their effects.

    “Furthermore, most GWAS associations map to the noncoding genome and thus lack a direct address to the gene that mediates their effects.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Other pleiotropic relationships connect diseases and traits in surprising ways, highlighting shared polygenic effects and cell-type specificity and delivering insights into shared biology and overlapping mechanisms.

    “Others connect diseases and traits in surprising ways, highlighting shared polygenic, pleiotropic effects and cell-type specificity, and delivering insights into shared biology and overlapping mechanisms86,87.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [86] Kanai, M. et al. Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat. Genet. 50, 390–400 (2018). source

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    • cites [87] Gudmundsson, J. et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat. Genet. 39, 977–983 (2007). source

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  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    These developments are rapidly converging towards a comprehensive matrix of the effect of all observable genetic variants across the widest possible range of cross-sectional and longitudinal biomedical phenotypes.

    “These developments are rapidly converging towards the ultimate destination: a comprehensive matrix of the effect of all observable genetic variants across the widest possible range of cross-sectional and longitudinal biomedical phenotypes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Somatic cancer testing has increased as therapies targeting specific mutational events entered clinical practice.

    “In parallel, the use of somatic cancer testing has increased as therapies targeted to specific mutational events have entered clinical practice (these developments are reviewed elsewhere131,132).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [131] Ding, L. et al. Perspective on oncogenic processes at the end of the beginning of cancer genomics. Cell 173, 305–320 (2018). source

      Not checked in the free run.

    • cites [132] Chae, Y. K. et al. Path toward precision oncology: review of targeted therapy studies and tools to aid in defining “actionability” of a molecular lesion and patient management support. Mol. Cancer Ther. 16, 2645–2655 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Prenatal testing may be more effective at avoiding disease than other approaches, but its ethical issues are more complex.

    “Whereas prenatal testing may be more effective at avoiding disease, the associated ethical issues are more complex144.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Bauer, P. E. “Tell them it’s not so bad”: prenatal screening for Down syndrome and the bias toward abortion. Intellect. Dev. Disabil. 46, 247–251 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deep sequencing of affected tissues for mosaic variants and RNA sequencing for noncoding variants are new fronts in clinical diagnostics.

    “Deep sequencing of affected tissues for mosaic variants and the use of RNA sequencing to detect noncoding variants that drive early-onset disease (for example, through effects on splicing) represent new fronts for clinical diagnostics30.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Cummings, B. B. et al. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci. Transl. Med. 9, eaal5209 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Noninvasive prenatal testing had exceeded ten million tests by 2018 across multiple countries.

    “Other examples of the rapid adoption of new genomic technologies include noninvasive prenatal testing (more than ten million tests by 2018 across multiple countries139–141) and the use of recessive carrier panels for couples planning pregnancies.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [139] Liu, S. et al. Genomic analyses from non-invasive prenatal testing reveal genetic associations, patterns of viral infections, and Chinese population history. Cell 175, 347–359 (2018). source

      Not checked in the free run.

    • cites [140] Thung, D. T., Beulen, L., Hehir-Kwa, J. & Faas, B. H. Implementation of whole genome massively parallel sequencing for noninvasive prenatal testing in laboratories. Expert Rev. Mol. Diagn. 15, 111–124 (2015). source

      Not checked in the free run.

    • cites [141] Lo, J. O., Cori D, F., Norton, M. E. & Caughey, A. B. Noninvasive prenatal testing. Obstet. Gynecol. Surv. 69, 89–99 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Newborn screening is universal in many countries but limited to disorders with high-throughput low-cost detection and effective early interventions.

    “Newborn screening is now universal in many countries, although it is limited to disorders combining high-throughput low-cost detection with effective early interventions (such as diet restrictions or enzyme replacement)142.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Watson, M. S. et al. Newborn screening: toward a uniform screening panel and system—executive summary. Pediatrics 117, S296–S307 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Parent-offspring trio sequencing can detect de novo variation in dominant disorders and phase biallelic rare variants in recessive disease.

    “Sequencing of the parent–offspring trio can detect de novo variation in dominant disorders and phase biallelic rare variants in recessive disease13.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Vissers, L. E. et al. A de novo paradigm for mental retardation. Nat. Genet. 42, 1109–1112 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There are more than 50 FDA-approved drugs for genetic disorders.

    “There is a growing list of diseases for which a molecular diagnosis results in specific interventions designed to improve patient outcomes (https://www.ncbi.nlm.nih.gov/books/NBK1116/) (some examples are listed in Table 1), and there are currently more than 50 FDA-approved drugs for genetic disorders155.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] CenterWatch. FDA Approved Drugs for Genetic Disease (CenterWatch); https://www.centerwatch.com/drug-information/fda-approved-drugs/therapeutic-area/34/genetic-disease

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Over the past two decades, understanding of the genetic basis of human disease has been transformed by technological and analytical advances, collaborative resource development, and large-scale data collection and analysis.

    “Over the past two decades, understanding of the genetic basis of human disease has been transformed by a combination of spectacular technological and analytical advances, collaborative commitment to the development of foundational resources and the collection and analysis of vast amounts of genetic, molecular and clinical data.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Gene therapy has evolved slowly since its introduction, but recent gene editing advances are reinvigorating treatment approaches by manipulating underlying genetic defects.

    “Although gene therapy has been slow to evolve since its early introduction, recent advances in gene editing are reinvigorating approaches to treat disorders by manipulation of the underlying genetic defects156.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Wu, Y. et al. Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nat. Med. 25, 776–783 (2019). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    Biological insights from genetic and molecular data are increasingly driving translational innovation, and wider personal access to such data promises to reshape medical care.

    “The biological insights derived from these data are, increasingly, drivers of translational innovation, and widening personal access to large-scale genetic and molecular data promises to reshape medical care.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    For drug targets that have supportive evidence from human genetics, the probability of therapeutic success is increased by roughly a factor of two.

    “An influential paper that demonstrates that the probability of therapeutic success is enhanced (by around a factor of 2) for drug targets with supportive evidence from human genetics.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Nelson, M. R. et al. The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856–860 (2015). An influential paper that demonstrates that the probability of therapeutic success is enhanced (by around a factor of 2) for drug targets with supportive evidence from human genetics. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The historical concentration of genetic discovery on populations of European descent has adverse consequences for both discovery and translation.

    “An elegant distillation of the ways in which the historical focus of genetic discovery among populations of European descent has adverse consequences for both discovery and translation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Martin, A. R. et al. Clinical use of current polygenic risk scores may exacerbate health disparities. Nat. Genet. 51, 584–591 (2019). An elegant distillation of the ways in which the historical focus of genetic discovery among populations of European descent has adverse consequences for both discovery and translation. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many healthcare professionals lack experience in genomic medicine and need education and guidance.

    “Many healthcare professionals lack experience in genomic medicine and need education and guidance to practice in the rapidly evolving space of genetic and genomic testing149.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Katz, S. J. et al. Association of attending surgeon with variation in the receipt of genetic testing after diagnosis of breast cancer. JAMA Surg. 153, 909–916 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The direct-to-consumer testing market has expanded, is variably controlled by country-specific regulations, and is moving toward models with direct access to ordering physicians and genetic counselors.

    “One consequence of these difficulties has been an expanding direct-to-consumer testing market, variably controlled by country-specific regulations150, which is moving beyond a focus on ancestry and personal traits, towards models in which individuals have direct access to ordering physicians and genetic counselors151.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [150] Kalokairinou, L. et al. Legislation of direct-to-consumer genetic testing in Europe: a fragmented regulatory landscape. J. Community Genet. 9, 117–132 (2018). source

      Not checked in the free run.

    • cites [151] Allyse, M. A., Robinson, D. H., Ferber, M. J. & Sharp, R. R. Direct-to-Consumer Testing 2.0: emerging models of direct-to-consumer genetic testing. Mayo Clin. Proc. 93, 113–120 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    Realizing the full potential of genomic medicine requires sustained collaborative work to produce a comprehensive understanding of disease mechanisms that can be translated into future medicines.

    “However, for the full potential of genomic medicine to be realized, there will need to be sustained collaborative endeavour on several fronts to ensure that the capacity to generate ever more detailed maps of the relationships between sequence variation and biomedical phenotypes delivers a comprehensive understanding of disease mechanisms that can be translated into the medicines of tomorrow.”
    Quote in the paperNot a substantial claim
54 of 54

  • The paper relies on this without support.

    For almost all human diseases, individual susceptibility is influenced to some degree by genetic variation.

    “For almost all human diseases, individual susceptibility is, to some degree, influenced by genetic variation.”

  • The paper relies on this without support.

    Inherited sequence variation is a prominent cause of phenotypic variation, while phenotypic variation does not cause inherited sequence variation.

    “as inherited sequence variation is a prominent cause of phenotypic variation (but the reverse is not true)”

  • The paper relies on this without support.

    Patterns of genetic predisposition are broadly similar across major population groups.

    “Whereas patterns of genetic predisposition appear broadly similar across major population groups”

  • The authors state this as an assumption.

    Most common disease-risk variants map to noncoding sequences and influence predisposition through effects on transcriptional regulation.

    “most common disease-risk variants map to noncoding sequences, and are presumed to influence predisposition through effects on transcriptional regulation.”

  • The paper relies on this without support.

    The limited heritability of many multifactorial traits constrains the clinical precision available from genetic data alone.

    “The limited heritability of many multifactorial traits constrains the clinical precision available from genetic data alone.”

  • The paper relies on this without support.

    The absence of evidence-based guidelines to support healthcare recommendations hinders clinical applications of genetic data.

    “The absence of evidence-based guidelines to support healthcare recommendations continues to hinder the clinical applications of genetic data.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Functional studies that reveal how risk variants contribute to disease lag far behind the rapidly growing catalogue of genetic risk variants.

    “While the catalogue of such risk variants is growing rapidly, functional studies that uncover how these variants contribute to disease are lagging far behind1–3.”

    From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [2]

  • The rate of new causal gene identification for rare blood disorders has been incredible in the past decade as a result of advances in massively parallel sequencing.

    “The rate of new causal gene identification for such disorders, as with many other rare diseases, has been incredible in the past decade as a result of advances in massively parallel sequencing (Claussnitzer et al., 2020).”

    From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Claussnitzer et al., 2020

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Authors
Claussnitzer, M., Cho, J. H., Collins, R., Cox, N. J., Dermitzakis, E. T., Hurles, M. E., Kathiresan, S., Kenny, E. E., Lindgren, C. M., MacArthur, D. G., North, K. N., Plon, S. E., Rehm, H. L., Risch, N., Rotimi, C. N., Shendure, J., Soranzo, N., & McCarthy, M. I.
Affiliations
  • Broad Institute (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Oxford (GB)
  • Vanderbilt University (US)
  • University of Geneva (CH)
  • Wellcome Sanger Institute (GB)
  • The University of Melbourne (AU)
  • Baylor College of Medicine (US)
  • University of California, San Francisco (US)
  • National Institutes of Health (US)
  • Howard Hughes Medical Institute (US)
  • University of Cambridge (GB)
  • Centre for Human Genetics (GB)
Corresponding author
McCarthy, Mark I.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-01-08
Volume
577
Issue
7789
Pages
179-189
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-019-1879-7
PMC
PMC7405896
OpenAlex
W2999574254
Semantic Scholar
fb9d4cf6d6890324448cfb8116e93082aaf8fb08
Cited by
697
References
181
Citations by year
2026: 68 · 2025: 95 · 2024: 127 · 2023: 115 · 2022: 120 · 2021: 108 · 2020: 62 · 2019: 1
FWCI
14.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders
  • National Science Foundation
  • Howard Hughes Medical Institute
  • Leona M. and Harry B. Helmsley Charitable Trust (U01DK062422)
  • Li Ka Shing Foundation
  • Wellcome Trust (212259, 098381, 090532, 203141, 106130/Z/14/Z, 106130)
  • Broad Institute
  • National Institute for Health and Care Research (NF-SI-0617-10090)
  • British Heart Foundation (CH/1996001/9454)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • National Institutes of Health
  • National Health and Medical Research Council (1113531)
  • NIHR Oxford Biomedical Research Centre
  • National Heart, Lung, and Blood Institute (R01HL104608)
  • National Institute of Mental Health (R01MH113362)
  • National Human Genome Research Institute (R01HG010297, U01HG009086, U01HG006485, U01HG009610, U01HG009080, U41HG009649)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01DK085545, U01DK105535, R01DK110113, R01DK098032, R01DK106593, U01DK062429, U24DK062429, U01DK062422)
  • National Institute on Minority Health and Health Disparities (U54MD010722)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD028138)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
human disease genetics, DNA sequence variants, genetic susceptibility, rare diseases, common diseases, disease mechanisms, personalized medicine, genotype-phenotype data, genomic resources
MeSH terms
Animals, Genetic Testing, Genotype, Humans, Phenotype, Genetic Variation, Genomics, Rare Diseases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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