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Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank

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Szustakowski, Joseph D., Balasubramanian, Suganthi, Kvikstad, Erika, Khalid, Shareef, Bronson, Paola G., Sasson, Ariella, Wong, Emily, Liu, Daren +104 more·2021·Nature Genetics
DOI 10.1038/s41588-021-00885-0

Published version of a preprint

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Abstract

The UK Biobank Exome Sequencing Consortium (UKB-ESC) is a private–public partnership between the UK Biobank (UKB) and eight biopharmaceutical companies that will complete the sequencing of exomes for all ~500,000 UKB participants. Here, we describe the early results from ~200,000 UKB participants and the features of this project that enabled its success. The biopharmaceutical industry has increasingly used human genetics to improve success in drug discovery. Recognizing the need for large-scale human genetics data, as well as the unique value of the data access and contribution terms of the UKB, the UKB-ESC was formed. As a result, exome data from 200,643 UKB enrollees are now available. These data include ~10 million exonic variants—a rich resource of rare coding variation that is particularly valuable for drug discovery. The UKB-ESC precompetitive collaboration has further strengthened academic and industry ties and has provided teams with an opportunity to interact with and learn from the wider research community. The UK Biobank Exome Sequencing Consortium aims to sequence all the exomes of approximately 500,000 UK Biobank participants. This Perspective describes the results from approximately 200,000 exomes and discusses the lessons learned from this UK Biobank–biopharmaceutical company collaboration.

AI snapshot

Written from the paper’s full text.

TL;DR

The UK Biobank Exome Sequencing Consortium generated and released exome sequencing data for the first 200,643 UK Biobank participants, observing ~10M variants in targeted regions. The resource is intended to enable rare-variant human genetics studies and drug discovery, with coding variants and predicted loss-of-function variation characterized at scale.

Key findings

The first 200,643 UKB exomes covered a targeted region of 38,997,831 bases, with coverage exceeding 20X on 95.6% of sites on average; ~10M variants were observed, including 8,086,176 SNPs, 370,958 indels, and 1,596,984 multi-allelic variants.

  • Of the ~8M SNPs observed, 84.5% were coding: 2,139,318 (25.3%) synonymous, 4,549,694 (53.8%) missense, and 453,733 (5.4%) predicted loss-of-function (LOF) variants affecting at least one coding transcript.
  • Allele frequencies were skewed rare: 98% of synonymous, 99% of missense, and 99% of LOF variants had MAF <1%. Per individual, medians were 8,586 synonymous, 7,724 missense, and 202 LOF variants; restricting to canonical transcripts gave a median of 142 LOFs per individual.
  • Genes with heterozygous LOF variants increased modestly from 17,718 in UKB 50K to 18,045 in UKB 200K; genes with at least one homozygous LOF were 1,492 in UKB 200K, with a projection of 1,981 in 500K.

Methods

The OQFE protocol mapped raw FASTQ reads with BWA-MEM to GRCh38, retained supplementary alignments, added mate tags with samblaster, marked duplicates with Picard 2.21.2, and compressed final CRAMs with samtools.

  • The OQFE pipeline was applied to more than 200,000 UKB exome samples; variants were called per CRAM with DeepVariant 0.10.0 using a model retrained on exome data, restricted to the exome capture region plus 100 bp flanks, and gVCFs were merged with GLnexus 1.2.6 using default “DeepVariantWES” parameters.
  • QC included individual and variant missingness <10%, Hardy-Weinberg equilibrium p>10^-15, minimum depth of 7 for SNPs and 10 for indels, and allele balance >0.15 for SNPs and >0.20 for indels; annotation used SnpEff with Ensembl 85, canonical transcripts from MANE Select v0.9/APPRIS/Ensembl, and a strict LOF subset.

Limitations

The paper does not state a formal limitations section.

  • Evident from the text: exome sequencing is restricted to targeted coding regions plus 100 bp flanks, so noncoding and broader variation are not captured; the reported data are for the first 200,643 exomes, with 500K figures presented as projections rather than observed results.
  • Evident from the text: the sequenced cohort is predominantly European ancestry (93.7% in UKB 200K; 94.0% in UKB 500K), and phenotypes are defined using ICD10 codes plus self-reported questionnaire data, which may limit generalizability and phenotype precision; the paper also notes that identifying true LOF events is not straightforward and uses a strict LOF subset.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41588-021-00885-0

Cites

121 of 121 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

No claims could be anchored to a verbatim quote in the text.

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?

  • Almost all UK Biobank participants underwent genome-wide array genotyping and, more recently, proteome, whole-exome sequencing and whole-genome sequencing.

    “Further, almost all participants underwent genome-wide array genotyping and, more recently, proteome, whole-exome sequencing 83 and WGS 84 .”

    From Multimodal biomedical AI (2022) · cites this paper as [83]

    Citation 83 is attached to whole-exome sequencing. The Abstract reports exome data for the first roughly 200,000 of approximately 500,000 UK Biobank participants and says sequencing all participants was a future goal. It supports that exome sequencing had occurred, but not that almost all participants had undergone it; the separate citation 84 is attached to whole-genome sequencing. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Targeted-region variant total is overstated

    Minor

    The text reports approximately 10 million variants within the targeted regions, but the table gives 8,457,134. The table's SNP and indel counts sum exactly to 8,457,134, so the multi-allelic sites cannot be added as a separate category to reach 10 million.

  • Synonymous percentage does not match the stated SNP denominator

    Minor

    The sentence describes percentages of the approximately 8 million SNPs. On that denominator, 2,139,318 synonymous variants are 26.46%, not 25.3%; 25.3% instead uses the table's larger targeted-region variant total.

    Reported 25.3 · recomputed 26.456486

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Cites

Flagged first, then by citations

Research works printed but not linked: 97

  1. Cingolani, P., Platts, A., Wang, L. L., Coon, M., Nguyen, T., Wang, L., Land, S. J., Lu, X., & Ruden, D. M. (2012). A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso- 2; iso-3. Fly, 6(2). https://doi.org/10.4161/fly.19695 · DOI · Paper page
  2. Aartsma-Rus, A. (2018). Genetic therapies for spinal muscular atrophy type 1. In The Lancet Neurology (Vol. 17, Issue 2, pp. 111-112). Lancet Publishing Group. https://doi.org/10.1016/S1474-4422(17)30436-2 · DOI
  3. Abifadel, M., Varret, M., Rabès, J. P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derré, A., Villéger, L., Farnier, M., Beucler, I., Bruckert, E., Chambaz, J., Chanu, B., Lecerf, J. M., Luc, G., … Boileau, C. (2003). Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics, 34(2), 154- 156. https://doi.org/10.1038/ng1161 · DOI · Paper page
  4. Abul-Husn, N. S., Cheng, X., Li, A. H., Xin, Y., Schurmann, C., Stevis, P., Liu, Y., Kozlitina, J., Stender, S., Wood, G. C., Stepanchick, A. N., Still, M. D., McCarthy, S., O'Dushlaine, C., Packer, J. S., Balasubramanian, S., Gosalia, N., Esopi, D., Kim, S. Y., … Dewey, F. E. (2018). A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease. New England Journal of Medicine, 378(12), 1096-1106. https://doi.org/10.1056/NEJMoa1712191 · DOI · Paper page
  5. Aittomäki, K., Dieguez Lucena, J., Pakarinen, P., Sistonen, P., Tapanainen, J., Gromoll, J., Kaskikari, R., Sankila, E. M., Lehväslaiho, H., Reyes Engel, A., Nieschlag, E., Huhtaniemi, I., & de la Chapelle, A. (1995). Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell, 82(6), 959-968. https://doi.org/10.1016/0092-8674(95)90275-9 · DOI
  6. Andersson, S., Berman, D. M., Jenkins, E. P., & Russell, D. W. (1991). Deletion of steroid 5α- reductase 2 gene in male pseudohermaphroditism. Nature, 354(6349), 159-161. https://doi.org/10.1038/354159a0 · DOI · Paper page
  7. Auton, A., Abecasis, G. R., Altshuler, D. M., Durbin, R. M., Bentley, D. R., Chakravarti, A., Clark, A. G., Donnelly, P., Eichler, E. E., Flicek, P., Gabriel, S. B., Gibbs, R. A., Green, E. D., Hurles, M. E., Knoppers, B. M., Korbel, J. O., Lander, E. S., Lee, C., Lehrach, H., … Schloss, J. A. (2015). A global reference for human genetic variation. In Nature (Vol. 526, Issue 7571, pp. 68-74). Nature Publishing Group. https://doi.org/10.1038/nature15393 · DOI · Paper page
  8. Ay Ling, R. M., Ross, R., Towner, P., Von Laue, S., Finidori, J., Moutoussamy, S., Buchanan, C. R., Clayton, P. E., & Norman, M. R. (1997). A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nature Genetics, 16(1), 13-14. https://doi.org/10.1038/ng0597-13 · DOI
  9. Bai, M., Quinn, S., Trivedi, S., Kifor, O., Pearce, S. H. S., Pollak, M. R., Krapcho, K., Hebert, S. C., & Brown, E. M. (1996). Expression and characterization of inactivating and activating mutations in the human Ca2+(o)-sensing receptor. Journal of Biological Chemistry, 271(32), 19537-19545. https://doi.org/10.1074/jbc.271.32.19537 · DOI
  10. Berndt, S. I., Skibola, C. F., Joseph, V., Camp, N. J., Nieters, A., Wang, Z., Cozen, W., Monnereau, A., Wang, S. S., Kelly, R. S., Lan, Q., Teras, L. R., Chatterjee, N., Chung, C. C., Yeager, M., Brooks-Wilson, A. R., Hartge, P., Purdue, M. P., Birmann, B. M., … Slager, S. L. (2013). Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia. Nature Genetics, 45(8), 868-876. https://doi.org/10.1038/ng.2652 · DOI
  11. Bichet, D. G., Birnbaumer, M., Lonergan, M., Arthus, M. F., Rosenthal, W., Goodyer, P., Nivet, H., Benoit, S., Giampietro, P., Simonetti, S., Fish, A., Whitley, C. B., Jaeger, P., Gertner, J., New, M., DiBona, F. J., Kaplan, B. S., Robertson, G. L., Hendy, G. N., … Morgan, K. (1994). Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus. American Journal of Human Genetics, 55(2), 278-286.
  12. Burkhardt, R., Kenny, E. E., Lowe, J. K., Birkeland, A., Josowitz, R., Noel, M., Salit, J., Maller, J. B., Pe'er, I., Daly, M. J., Altshuler, D., Stoffel, M., Friedman, J. M., & Breslow, J. L. (2008). Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(11), 2078-2084. https://doi.org/10.1161/ATVBAHA.108.172288 · DOI
  13. Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., Ouwehand, W. H., Samani, N. J., Todd, J. A., Donnelly, P., Barrett, J. C., Davison, D., Easton, D., Evans, D., Leung, H. T., Marchini, J. L., Morris, A. P., … Compston, A. (2007). Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature, 447(7145), 661-678. https://doi.org/10.1038/nature05911 · DOI · Paper page
  14. Bycroft, C., Freeman, C., Petkova, D., Band, G., Elliott, L. T., Sharp, K., Motyer, A., Vukcevic, D., Delaneau, O., O'Connell, J., Cortes, A., Welsh, S., Young, A., Effingham, M., McVean, G., Leslie, S., Allen, N., Donnelly, P., & Marchini, J. (2018). The UK Biobank resource with deep phenotyping and genomic data. Nature, 562(7726), 203-209. https://doi.org/10.1038/s41586-018-0579-z · DOI · Paper page
  15. Cargill, M., Schrodi, S. J., Chang, M., Garcia, V. E., Brandon, R., Callis, K. P., Matsunami, N., Ardlie, K. G., Civello, D., Catanese, J. J., Leong, D. U., Panko, J. M., McAllister, L. B., Hansen, C. B., Papenfuss, J., Prescott, S. M., White, T. J., Leppert, M. F., Krueger, G. G., & Begovich, A. B. (2007). A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. American Journal of Human Genetics, 80(2), 273-290. https://doi.org/10.1086/511051 · DOI · Paper page
  16. Carrington, M., Kissner, T., Gerrard, B., Ivanov, S., O'Brien, S. J., & Dean, M. (1997). Novel alleles of the chemokine-receptor gene CCR5. American Journal of Human Genetics, 61(6), 1261- 1267. https://doi.org/10.1086/301645 · DOI
  17. Carroll, P., Al-Mojalli, H., Al-Abbad, A., Al-Hassoun, I., Al-Hamed, M., Al-Amr, R., Butt, A. I., & Meyer, B. F. (2006). Novel mutations underlying nephrogenic diabetes insipidus in Arab families. Genetics in Medicine, 8(7), 443-447. https://doi.org/10.1097/01.gim.0000223554.46981. · DOI
  18. Cattaneo, M. (2011). The platelet P2Y12 receptor for adenosine diphosphate: Congenital and drug-induced defects. In Blood (Vol. 117, Issue 7, pp. 2102-2112). Blood. https://doi.org/10.1182/blood-2010-08-263111 · DOI
  19. Chou, Y. H. W., Pollak, M. R., Brandi, M. L., Toss, G., Arnqvist, H., Atkinson, A. B., Papapoulos, S. E., Marx, S., Brown, E. M., Seidman, J. G., & Seidman, C. E. (1995). Mutations in the human Ca2+-sensing-receptor gene that cause familial hypocalciuric hypercalcemia. American Journal of Human Genetics, 56(5), 1075-1079.
  20. Cingolani, P., Platts, A., Wang, L. L., Coon, M., Nguyen, T., Wang, L., Land, S. J., Lu, X., & Ruden, D. M. (2012). A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso- 2; iso-3. Fly, 6(2). https://doi.org/10.4161/fly.19695 · DOI · Paper page
  21. Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., & Hobbs, H. H. (2005). Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nature Genetics, 37(2), 161-165. https://doi.org/10.1038/ng1509 · DOI · Paper page
  22. Cole, D. E. C., Yun, F. H. J., Wong, B. Y. L., Shuen, A. Y., Booth, R. A., Scillitani, A., Pidasheva, S., Zhou, X., Canaff, L., & Hendy, G. N. (2009). Calcium-sensing receptor mutations and denaturing high performance liquid chromatography. Journal of Molecular Endocrinology, 42(4), 331-339. https://doi.org/10.1677/JME-08-0164 · DOI
  23. Colombo, C., Porzio, O., Liu, M., Massa, O., Vasta, M., Salardi, S., Beccaria, L., Monciotti, C., Toni, S., Pedersen, O., Hansen, T., Federici, L., Pesavento, R., Cadario, F., Federici, G., Ghirri, P., Arvan, P., Iafusco, D., & Barbetti, F. (2008). Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. Journal of Clinical Investigation, 118(6), 2148-2156. https://doi.org/10.1172/JCI33777 · DOI
  24. Cook, D., Brown, D., Alexander, R., March, R., Morgan, P., Satterthwaite, G., & Pangalos, M. N. (2014). Lessons learned from the fate of AstraZeneca's drug pipeline: A five-dimensional framework. In Nature Reviews Drug Discovery (Vol. 13, Issue 6, pp. 419-431). Nature Publishing Group. https://doi.org/10.1038/nrd4309 · DOI · Paper page
  25. Dolgin, E. (2019). Massive NIH-industry project opens portals to target validation. Nature Reviews Drug Discovery. https://doi.org/10.1038/d41573-019-00033-8 · DOI
  26. Dunham, I., Kundaje, A., Aldred, S. F., Collins, P. J., Davis, C. A., Doyle, F., Epstein, C. B., Frietze, S., Harrow, J., Kaul, R., Khatun, J., Lajoie, B. R., Landt, S. G., Lee, B. K., Pauli, F., Rosenbloom, K. R., Sabo, P., Safi, A., Sanyal, A., … Lochovsky, L. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature, 489(7414), 57-74. https://doi.org/10.1038/nature11247 · DOI · Paper page
  27. Edghill, E. L., Flanagan, S. E., Patch, A. M., Boustred, C., Parrish, A., Shields, B., Shepherd, M. H., Hussain, K., Kapoor, R. R., Malecki, M., MacDonald, M. J., Støy, J., Steiner, D. F., Philipson, L. H., Bell, G. I., Hattersley, A. T., & Ellard, S. (2008). Insulin mutation screening in 1,044 patients with diabetes mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes, 57(4), 1034-1042. https://doi.org/10.2337/db07-1405 · DOI · Paper page
  28. Estrada, K., Styrkarsdottir, U., Evangelou, E., Hsu, Y. H., Duncan, E. L., Ntzani, E. E., Oei, L., Albagha, O. M. E., Amin, N., Kemp, J. P., Koller, D. L., Li, G., Liu, C. T., Minster, R. L., Moayyeri, A., Vandenput, L., Willner, D., Xiao, S. M., Yerges-Armstrong, L. M., … Rivadeneira, F. (2012). Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nature Genetics, 44(5), 491-501. https://doi.org/10.1038/ng.2249 · DOI
  29. Eyre, S., Bowes, J., Diogo, D., Lee, A., Barton, A., Martin, P., Zhernakova, A., Stahl, E., Viatte, S., McAllister, K., Amos, C. I., Padyukov, L., Toes, R. E. M., Huizinga, T. W. J., Wijmenga, C., Trynka, G., Franke, L., Westra, H. J., Alfredsson, L., … Bentley, D. (2012). High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nature Genetics, 44(12), 1336-1340. https://doi.org/10.1038/ng.2462 · DOI · Paper page
  30. Flannick, J., Mercader, J. M., Fuchsberger, C., Udler, M. S., Mahajan, A., Wessel, J., Teslovich, T. M., Caulkins, L., Koesterer, R., Barajas-Olmos, F., Blackwell, T. W., Boerwinkle, E., Brody, J. A., Centeno-Cruz, F., Chen, L., Chen, S., Contreras-Cubas, C., Córdova, E., Correa, A., … Boehnke, M. (2019). Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature, 570(7759), 71-76. https://doi.org/10.1038/s41586-019-1231-2 · DOI · Paper page
  31. Furtado, R. H. M., & Giugliano, R. P. (2020). What Lessons Have We Learned and What Remains to be Clarified for PCSK9 Inhibitors? A Review of FOURIER and ODYSSEY Outcomes Trials. Cardiology and Therapy, 1-15. https://doi.org/10.1007/s40119-020-00163-w · DOI
  32. Giri, A., Hellwege, J. N., Keaton, J. M., Park, J., Qiu, C., Warren, H. R., Torstenson, E. S., Kovesdy, C. P., Sun, Y. V., Wilson, O. D., Robinson-Cohen, C., Roumie, C. L., Chung, C. P., Birdwell, K. A., Damrauer, S. M., DuVall, S. L., Klarin, D., Cho, K., Wang, Y., … Edwards, T. L. (2019). Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nature Genetics, 51(1), 51-62. https://doi.org/10.1038/s41588-018-0303-9 · DOI
  33. Goddard, A. D., Covello, R., Luoh, S. M., Clackson, T., Attie, K. M., Gesundheit, N., Rundle, A. C., Wells, J. A., & Carlsson, L. M. S. (1995). Mutations of the growth hormone receptor in children with idiopathic short stature. New England Journal of Medicine, 333(17), 1093- 1098. https://doi.org/10.1056/NEJM199510263331701 · DOI
  34. Hamersma, H., Gardner, J., & Beighton, P. (2003). The natural history of sclerosteosis. Clinical Genetics, 63(3), 192-197. https://doi.org/10.1034/j.1399-0004.2003.00036.x · DOI
  35. Hinds, D. A., Buil, A., Ziemek, D., Martinez-Perez, A., Malik, R., Folkersen, L., Germain, M., Mälarstig, A., Brown, A., Soria, J. M., Dichgans, M., Bing, N., Franco-Cereceda, A., Souto, J. C., Dermitzakis, E. T., Hamsten, A., Worrall, B. B., Tung, J. Y., & Sabater-Lleal, M. (2016). Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis. Human Molecular Genetics, 25(9), 1867-1874. https://doi.org/10.1093/hmg/ddw037 · DOI
  36. Hoffmann, T. J., Ehret, G. B., Nandakumar, P., Ranatunga, D., Schaefer, C., Kwok, P. Y., Iribarren, C., Chakravarti, A., & Risch, N. (2017). Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation. Nature Genetics, 49(1), 54-64. https://doi.org/10.1038/ng.3715 · DOI
  37. Imperato-McGinley, J., Guerrero, L., Gautier, T., & Peterson, R. E. (1974). Steroid 5α-reductase deficiency in man: An inherited form of male pseudohermaphroditism. Science, 186(4170), 1213-1215. https://doi.org/10.1126/science.186.4170.1213 · DOI · Paper page
  38. Kathiresan, S., Melander, O., Guiducci, C., Surti, A., Burtt, N. P., Rieder, M. J., Cooper, G. M., Roos, C., Voight, B. F., Havulinna, A. S., Wahlstrand, B., Hedner, T., Corella, D., Tai, E. S., Ordovas, J. M., Berglund, G., Vartiainen, E., Jousilahti, P., Hedblad, B., … Orho-Melander, M. (2008). Six new loci associated with blood low-density lipoprotein cholesterol, high- density lipoprotein cholesterol or triglycerides in humans. Nature Genetics, 40(2), 189- 197. https://doi.org/10.1038/ng.75 · DOI · Paper page
  39. Khatun, I., Walsh, M. T., & Hussain, M. M. (2013). Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia. Journal of Lipid Research, 54(6), 1541-1549. https://doi.org/10.1194/jlr.M031658 · DOI
  40. Kichaev, G., Bhatia, G., Loh, P. R., Gazal, S., Burch, K., Freund, M. K., Schoech, A., Pasaniuc, B., & Price, A. L. (2019). Leveraging Polygenic Functional Enrichment to Improve GWAS Power. American Journal of Human Genetics, 104(1), 65-75. https://doi.org/10.1016/j.ajhg.2018.11.008 · DOI · Paper page
  41. King, E. A., Wade Davis, J., & Degner, J. F. (2019). Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. PLoS Genetics, 15(12), e1008489. https://doi.org/10.1371/journal.pgen.1008489 · DOI · Paper page
  42. Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., Devon, K., Dewar, K., Doyle, M., Fitzhugh, W., Funke, R., Gage, D., Harris, K., Heaford, A., Howland, J., Kann, L., Lehoczky, J., Levine, R., McEwan, P., … Morgan, M. J. (2001). Initial sequencing and analysis of the human genome. Nature, 409(6822), 860-921. https://doi.org/10.1038/35057062 · DOI · Paper page
  43. Laufer, V. A., Tiwari, H. K., Reynolds, R. J., Danila, M. I., Wang, J., Edberg, J. C., Kimberly, R. P., Kottyan, L. C., Harley, J. B., Mikuls, T. R., Gregersen, P. K., Absher, D. M., Langefeld, C. D., Arnett, D. K., & Bridges, S. L. (2019). Genetic influences on susceptibility to rheumatoid arthritis in African-Americans. Human Molecular Genetics, 28(5), 858-874. https://doi.org/10.1093/hmg/ddy395 · DOI
  44. Li, Z., Chen, J., Yu, H., He, L., Xu, Y., Zhang, D., Yi, Q., Li, C., Li, X., Shen, J., Song, Z., Ji, W., Wang, M., Zhou, J., Chen, B., Liu, Y., Wang, J., Wang, P., Yang, P., … Shi, Y. (2017). Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia. Nature Genetics, 49(11), 1576-1583. https://doi.org/10.1038/ng.3973 · DOI · Paper page
  45. Lin, J. M., Wan, L., Tsai, Y. Y., Lin, H. J., Tsai, Y., Lee, C. C., Tsai, C. H., Tseng, S. H., & Tsai, F. J. (2008). Vascular Endothelial Growth Factor Gene Polymorphisms in Age-related Macular Degeneration. American Journal of Ophthalmology, 145(6). https://doi.org/10.1016/j.ajo.2008.01.027 · DOI
  46. Lin, M., Rodeh, O., Penn, J., Bai, X., Reid, J., Krasheninina, O., & Salerno, W. (2018). GLnexus: joint variant calling for large cohort sequencing. BioRxiv, 343970. https://doi.org/10.1101/343970 · DOI
  47. Liu, J. Z., Chen, C.-Y., Tsai, E. A., Whelan, C. D., Sexton, D., John, S., & Runz, H. (2020). The burden of rare protein-truncating genetic variants on human lifespan. BioRxiv, 2020.06.02.129908. https://doi.org/10.1101/2020.06.02.129908 · DOI
  48. Mahajan, A., Wessel, J., Willems, S. M., Zhao, W., Robertson, N. R., Chu, A. Y., Gan, W., Kitajima, H., Taliun, D., Rayner, N. W., Guo, X., Lu, Y., Li, M., Jensen, R. A., Hu, Y., Huo, S., Lohman, K. K., Zhang, W., Cook, J. P., … McCarthy, M. I. (2018). Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes article. Nature Genetics, 50(4), 559-571. https://doi.org/10.1038/s41588-018-0084-1 · DOI · Paper page
  49. McCarthy, M. I., Abecasis, G. R., Cardon, L. R., Goldstein, D. B., Little, J., Ioannidis, J. P. A., & Hirschhorn, J. N. (2008). Genome-wide association studies for complex traits: Consensus, uncertainty and challenges. Nature Reviews Genetics, 9(5), 356-369. https://doi.org/10.1038/nrg2344 · DOI · Paper page
  50. McCarthy, S., Das, S., Kretzschmar, W., Delaneau, O., Wood, A. R., Teumer, A., Kang, H. M., Fuchsberger, C., Danecek, P., Sharp, K., Luo, Y., Sidore, C., Kwong, A., Timpson, N., Koskinen, S., Vrieze, S., Scott, L. J., Zhang, H., Mahajan, A., … Marchini, J. (2016). A reference panel of 64,976 haplotypes for genotype imputation. Nature Genetics, 48(10), 1279-1283. https://doi.org/10.1038/ng.3643 · DOI · Paper page
  51. Messier, T. L., Wong, C. Y., Bovill, E. G., Long, G. L., & Church, W. R. (1996). Factor X Stockton: a mild bleeding diathesis associated with an active site mutation in factor X. Blood Coagulation & Fibrinolysis;: An International Journal in Haemostasis and Thrombosis, 7(1), 5-14.
  52. Methé, B. A., Nelson, K. E., Pop, M., Creasy, H. H., Giglio, M. G., Huttenhower, C., Gevers, D., Petrosino, J. F., Abubucker, S., Badger, J. H., Chinwalla, A. T., Earl, A. M., Fitzgerald, M. G., Fulton, R. S., Hallsworth-Pepin, K., Lobos, E. A., Madupu, R., Magrini, V., Martin, J. C., … White, O. (2012). A framework for human microbiome research. Nature, 486(7402), 215- 221. https://doi.org/10.1038/nature11209 · DOI · Paper page
  53. Morris, A. P., Voight, B. F., Teslovich, T. M., Ferreira, T., Segrè, A. V., Steinthorsdottir, V., Strawbridge, R. J., Khan, H., Grallert, H., Mahajan, A., Prokopenko, I., Kang, H. M., Dina, C., Esko, T., Fraser, R. M., Kanoni, S., Kumar, A., Lagou, V., Langenberg, C., … McCarthy, M. I. (2012). Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nature Genetics, 44(9), 981-990. https://doi.org/10.1038/ng.2383 · DOI · Paper page
  54. Morris, J. A., Kemp, J. P., Youlten, S. E., Laurent, L., Logan, J. G., Chai, R. C., Vulpescu, N. A., Forgetta, V., Kleinman, A., Mohanty, S. T., Sergio, C. M., Quinn, J., Nguyen-Yamamoto, L., Luco, A. L., Vijay, J., Simon, M. M., Pramatarova, A., Medina-Gomez, C., Trajanoska, K., … Richards, J. B. (2019). An atlas of genetic influences on osteoporosis in humans and mice. Nature Genetics, 51(2), 258-266. https://doi.org/10.1038/s41588-018-0302-x · DOI · Paper page
  55. Nelson, M. R., Tipney, H., Painter, J. L., Shen, J., Nicoletti, P., Shen, Y., Floratos, A., Sham, P. C., Li, M. J., Wang, J., Cardon, L. R., Whittaker, J. C., & Sanseau, P. (2015). The support of human genetic evidence for approved drug indications. Nature Genetics, 47(8), 856-860. https://doi.org/10.1038/ng.3314 · DOI · Paper page
  56. Nestorowicz, A., Wilson, B. A., Schoor, K. P., Inoue, H., Glaser, B., Landau, H., Stanley, C. A., Thornton, P. S., Clement IV, J. P., Bryan, J., Aguilar-Bryan, L., & Permutt, M. A. (1996). Mutations in the sulfonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Human Molecular Genetics, 5(11), 1813-1822. https://doi.org/10.1093/hmg/5.11.1813 · DOI
  57. Nguyen, P. A., Born, D. A., Deaton, A. M., Nioi, P., & Ward, L. D. (2019). Phenotypes associated with genes encoding drug targets are predictive of clinical trial side effects. Nature Communications, 10(1). https://doi.org/10.1038/s41467-019-09407-3 · DOI
  58. Nioi, P., Sigurdsson, A., Thorleifsson, G., Helgason, H., Agustsdottir, A. B., Norddahl, G. L., Helgadottir, A., Magnusdottir, A., Jonasdottir, A., Gretarsdottir, S., Jonsdottir, I., Steinthorsdottir, V., Rafnar, T., Swinkels, D. W., Galesloot, T. E., Grarup, N., Jørgensen, T., Vestergaard, H., Hansen, T., … Stefansson, K. (2016). Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease. New England Journal of Medicine, 374(22), 2131-2141. https://doi.org/10.1056/NEJMoa1508419 · DOI · Paper page
  59. Nissen, P. H., Christensen, S. E., Heickendorff, L., Brixen, K., & Mosekilde, L. (2007). Molecular genetic analysis of the calcium sensing receptor gene in patients clinically suspected to have familial hypocalciuric hypercalcemia: Phenotypic variation and mutation spectrum in a Danish population. Journal of Clinical Endocrinology and Metabolism, 92(11), 4373-4379. https://doi.org/10.1210/jc.2007-0322 · DOI
  60. Novembre, J., Galvani, A. P., & Slatkin, M. (2005). The geographic spread of the CCR5 Δ32 HIV- resistance allele. PLoS Biology, 3(11), 1954-1962. https://doi.org/10.1371/journal.pbio.0030339 · DOI
  61. Okada, Y., Wu, D., Trynka, G., Raj, T., Terao, C., Ikari, K., Kochi, Y., Ohmura, K., Suzuki, A., Yoshida, S., Graham, R. R., Manoharan, A., Ortmann, W., Bhangale, T., Denny, J. C., Carroll, R. J., Eyler, A. E., Greenberg, J. D., Kremer, J. M., … Plenge, R. M. (2014). Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature, 506(7488), 376- 381. https://doi.org/10.1038/nature12873 · DOI · Paper page
  62. Otonkoski, T., Ämmälä, C., Huopio, H., Cote, G. J., Chapman, J., Cosgrove, K., Ashfield, R., Huang, E., Komulainen, J., Ashcroft, F. M., Dunne, M. J., Kere, J., & Thomas, P. M. (1999). A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland. Diabetes, 48(2), 408-415. https://doi.org/10.2337/diabetes.48.2.408 · DOI
  63. Pardiñas, A. F., Holmans, P., Pocklington, A. J., Escott-Price, V., Ripke, S., Carrera, N., Legge, S. E., Bishop, S., Cameron, D., Hamshere, M. L., Han, J., Hubbard, L., Lynham, A., Mantripragada, K., Rees, E., MacCabe, J. H., McCarroll, S. A., Baune, B. T., Breen, G., … Walters, J. T. R. (2018). Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nature Genetics, 50(3), 381-389. https://doi.org/10.1038/s41588-018-0059-2 · DOI · Paper page
  64. Poplin, R., Chang, P. C., Alexander, D., Schwartz, S., Colthurst, T., Ku, A., Newburger, D., Dijamco, J., Nguyen, N., Afshar, P. T., Gross, S. S., Dorfman, L., McLean, C. Y., & Depristo, M. A. (2018). A universal snp and small-indel variant caller using deep neural networks. Nature Biotechnology, 36(10), 983. https://doi.org/10.1038/nbt.4235 · DOI · Paper page
  65. Pullinger, C. R., Hennessy, L. K., Chatterton, J. E., Liu, W., Love, J. A., Mendel, C. M., Frost, P. H., Malloy, M. J., Schumaker, V. N., & Kane, J. P. (1995). Familial Ligand-Defective Apolipoprotein B: Identification of a New Mutation That Decreases LDL Receptor Binding Affinity. Journal of Clinical Investigation, 95(3), 1225-1234. https://doi.org/10.1172/JCI117772 · DOI
  66. Quillent, C., Oberlin, E., Braun, J., Rousset, D., Gonzalez-Canali, G., Métais, P., Montagnier, L., Virelizier, J. L., Arenzana-Seisdedos, F., & Beretta, A. (1998). HIV-1-resistance phenotype conferred by combination of two separate inherited mutations of CCR5 gene. Lancet, 351(9095), 14-18. https://doi.org/10.1016/S0140-6736(97)09185-X · DOI
  67. Regier, A. A., Farjoun, Y., Larson, D. E., Krasheninina, O., Kang, H. M., Howrigan, D. P., Chen, B. J., Kher, M., Banks, E., Ames, D. C., English, A. C., Li, H., Xing, J., Zhang, Y., Matise, T., Abecasis, G. R., Salerno, W., Zody, M. C., Neale, B. M., & Hall, I. M. (2018). Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects. Nature Communications, 9(1), 4038. https://doi.org/10.1038/s41467-018-06159-4 · DOI
  68. Ripke, S., Neale, B. M., Corvin, A., Walters, J. T. R., Farh, K. H., Holmans, P. A., Lee, P., Bulik- Sullivan, B., Collier, D. A., Huang, H., Pers, T. H., Agartz, I., Agerbo, E., Albus, M., Alexander, M., Amin, F., Bacanu, S. A., Begemann, M., Belliveau, R. A., … O'Donovan, M. C. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511(7510), 421- 427. https://doi.org/10.1038/nature13595 · DOI · Paper page
  69. Rodriguez, J. M., Rodriguez-Rivas, J., Di Domenico, T., Vázquez, J., Valencia, A., & Tress, M. L. (2018). APPRIS 2017: Principal isoforms for multiple gene sets. Nucleic Acids Research, 46(D1). https://doi.org/10.1093/nar/gkx997 · DOI
  70. Rosenthal, W., Seibold, A., Antaramian, A., Lonergan, M., Arthus, M. F., Hendy, G. N., Birnbaumer, M., & Bichet, D. G. (1992). Molecular identification of the gene responsible for congenital nephrogenic diabetes insipidus. Nature, 359(6392), 233-235. https://doi.org/10.1038/359233a0 · DOI
  71. Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., Kuder, J. F., Wang, H., Liu, T., Wasserman, S. M., Sever, P. S., Pedersen, T. R., Fish, M. P., Abrahamsen, T. E., Im, K., Kanevsky, E., Bonaca, M. P., Lira Pineda, A., Hanlon, K., … Shifrin, G. (2017). Evolocumab and clinical outcomes in patients with cardiovascular disease. New England Journal of Medicine, 376(18), 1713-1722. https://doi.org/10.1056/NEJMoa1615664 · DOI · Paper page
  72. Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Quintero, K., Roe, M. T., Sasiela, W. J., Tamby, J. F., … Ball, E. (2018). Alirocumab and cardiovascular outcomes after acute coronary syndrome. New England Journal of Medicine, 379(22), 2097-2107. https://doi.org/10.1056/NEJMoa1801174 · DOI · Paper page
  73. Sinner, M. F., Pfeufer, A., Akyol, M., Beckmann, B. M., Hinterseer, M., Wacker, A., Perz, S., Sauter, W., Illig, T., Näbauer, M., Schmitt, C., Wichmann, H. E., Schömig, A., Steinbeck, G., Meitinger, T., & Kääb, S. (2008). The non-synonymous coding IKr-channel variant KCNH2- K897T is associated with atrial fibrillation: Results from a systematic candidate gene-based analysis of KCNH2 (HERG). European Heart Journal, 29(7), 907-914. https://doi.org/10.1093/eurheartj/ehm619 · DOI
  74. Soria, L. F., Ludwig, E. H., Clarke, H. R. G., Vega, G. L., Grundy, S. M., & McCarthy, B. J. (1989). Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proceedings of the National Academy of Sciences of the United States of America, 86(2), 587-591. https://doi.org/10.1073/pnas.86.2.587 · DOI
  75. Stitziel, N. O., Won, H. H., Morrison, A. C., Peloso, G. M., Do, R., Lange, L. A., Fontanillas, P., Gupta, N., Duga, S., Goel, A., Farrall, M., Saleheen, D., Ferrario, P., König, I., Asselta, R., Merlini, P. A., Marziliano, N., Notarangelo, M. F., Schick, U., … Kathiresan, S. (2014). Inactivating mutations in NPC1L1 and protection from coronary heart disease. New England Journal of Medicine, 371(22), 2072-2082. https://doi.org/10.1056/NEJMoa1405386 · DOI · Paper page
  76. Støy, J., Edghill, E. L., Flanagan, S. E., Ye, H., Paz, V. P., Pluzhnikov, A., Below, J. E., Hayes, M. G., Cox, N. J., Lipkind, G. M., Lipton, R. B., Greeley, S. A. W., Patch, A. M., Ellard, S., Steiner, D. F., Hattersley, A. T., Philipson, L. H., & Bell, G. I. (2007). Insulin gene mutations as a cause of permanent neonatal diabetes. Proceedings of the National Academy of Sciences of the United States of America, 104(38), 15040-15044. https://doi.org/10.1073/pnas.0707291104 · DOI · Paper page
  77. Styrkarsdottir, U., Halldorsson, B. V., Gretarsdottir, S., Gudbjartsson, D. F., Walters, G. B., Ingvarsson, T., Jonsdottir, T., Saemundsdottir, J., Snorradóttir, S., Center, J. R., Nguyen, T. V., Alexandersen, P., Gulcher, J. R., Eisman, J. A., Christiansen, C., Sigurdsson, G., Kong, A., Thorsteinsdottir, U., & Stefansson, K. (2009). New sequence variants associated with bone mineral density. Nature Genetics, 41(1), 15-17. https://doi.org/10.1038/ng.284 · DOI
  78. Styrkarsdottir, U., Thorleifsson, G., Gudjonsson, S. A., Sigurdsson, A., Center, J. R., Lee, S. H., Nguyen, T. V., Kwok, T. C. Y., Lee, J. S. W., Ho, S. C., Woo, J., Leung, P. C., Kim, B. J., Rafnar, T., Kiemeney, L. A., Ingvarsson, T., Koh, J. M., Tang, N. L. S., Eisman, J. A., … Stefansson, K. (2016). Sequence variants in the PTCH1 gene associate with spine bone mineral density and osteoporotic fractures. Nature Communications, 7. https://doi.org/10.1038/ncomms10129 · DOI
  79. Sullivan, A. D., Wigginton, J., & Kirschner, D. (2001). The coreceptor mutation CCR5δ32 influences the dynamics of hiv epidemics and is selected for by HIV. Proceedings of the National Academy of Sciences of the United States of America, 98(18), 10214-10219. https://doi.org/10.1073/pnas.181325198 · DOI
  80. Sung, Y. J., Winkler, T. W., de las Fuentes, L., Bentley, A. R., Brown, M. R., Kraja, A. T., Schwander, K., Ntalla, I., Guo, X., Franceschini, N., Lu, Y., Cheng, C. Y., Sim, X., Vojinovic, D., Marten, J., Musani, S. K., Li, C., Feitosa, M. F., Kilpeläinen, T. O., … Chasman, D. I. (2018). A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. American Journal of Human Genetics, 102(3), 375-400. https://doi.org/10.1016/j.ajhg.2018.01.015 · DOI
  81. Takeuchi, F., Akiyama, M., Matoba, N., Katsuya, T., Nakatochi, M., Tabara, Y., Narita, A., Saw, W. Y., Moon, S., Spracklen, C. N., Chai, J. F., Kim, Y. J., Zhang, L., Wang, C., Li, H., Li, H., Wu, J. Y., Dorajoo, R., Nierenberg, J. L., … Kato, N. (2018). Interethnic analyses of blood pressure loci in populations of East Asian and European descent. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-07345-0 The Cancer Genome Atlas Program -National Cancer Institute. (n.d.). · DOI
  82. Thomas, P. M., Wohllk, N., Huang, E., Kuhnle, U., Rabl, W., Gagel, R. F., & Cote, G. J. (1996). Inactivation of the first nucleotide-binding fold of the sulfonylurea receptor, and familial persistent hyperinsulinemic hypoglycemia of infancy. American Journal of Human Genetics, 59(3), 510-518.
  83. Van Der Graaf, A., Avis, H. J., Kusters, D. M., Vissers, M. N., Hutten, B. A., Defesche, J. C., Huijgen, R., Fouchier, S. W., Wijburg, F. A., Kastelein, J. J. P., & Wiegman, A. (2011). Molecular basis of autosomal dominant hypercholesterolemia: Assessment in a large cohort of hypercholesterolemic children. Circulation, 123(11), 1167-1173. https://doi.org/10.1161/CIRCULATIONAHA.110.979450 · DOI
  84. Van Hout, C. V., Tachmazidou, I., Backman, J. D., Hoffman, J. D., Liu, D., Pandey, A. K., Gonzaga- Jauregui, C., Khalid, S., Ye, B., Banerjee, N., Li, A. H., O'Dushlaine, C., Marcketta, A., Staples, J., Schurmann, C., Hawes, A., Maxwell, E., Barnard, L., Lopez, A., … Baras, A. (2020). Exome sequencing and characterization of 49,960 individuals in the UK Biobank. Nature. https://doi.org/10.1038/s41586-020-2853-0 · DOI · Paper page
  85. Watzke, H. H., Lechner, K., Roberts, H. R., Reddy, S. V., Welsch, D. J., Friedman, P., Mahr, G., Jagadeeswaran, P., Monroe, D. M., & High, K. A. (1990). Molecular defect (Gla+14 → Lys) and its functional consequences in a hereditary factor X deficiency (factor X 'Vorarlberg'). Journal of Biological Chemistry, 265(20), 11982-11989.
  86. Willer, C. J., Schmidt, E. M., Sengupta, S., Peloso, G. M., Gustafsson, S., Kanoni, S., Ganna, A., Chen, J., Buchkovich, M. L., Mora, S., Beckmann, J. S., Bragg-Gresham, J. L., Chang, H. Y., Demirkan, A., Den Hertog, H. M., Do, R., Donnelly, L. A., Ehret, G. B., Esko, T., … Abecasis, G. R. (2013). Discovery and refinement of loci associated with lipid levels. Nature Genetics, 45(11), 1274-1285. https://doi.org/10.1038/ng.2797 · DOI
  87. Winkler, T. W., Justice, A. E., Graff, M., Barata, L., Feitosa, M. F., Chu, S., Czajkowski, J., Esko, T., Fall, T., Kilpeläinen, T. O., Lu, Y., Mägi, R., Mihailov, E., Pers, T. H., Rüeger, S., Teumer, A., Ehret, G. B., Ferreira, T., Heard-Costa, N. L., … Loos, R. J. F. (2015). The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. PLoS Genetics, 11(10), 1-42. https://doi.org/10.1371/journal.pgen.1005378 · DOI
  88. Wood, A. J. j., & Rittmaster, R. S. (1994). Finasteride. In New England Journal of Medicine (Vol. 330, Issue 2, pp. 120-125). https://doi.org/10.1056/NEJM199401133300208 · DOI
  89. Xiong, H. Y., Alipanahi, B., Lee, L. J., Bretschneider, H., Merico, D., Yuen, R. K. C., Hua, Y., Gueroussov, S., Najafabadi, H. S., Hughes, T. R., Morris, Q., Barash, Y., Krainer, A. R., Jojic, N., Scherer, S. W., Blencowe, B. J., & Frey, B. J. (2015). The human splicing code reveals new insights into the genetic determinants of disease. Science, 347(6218). https://doi.org/10.1126/science.1254806 · DOI
  90. Xue, A., Wu, Y., Zhu, Z., Zhang, F., Kemper, K. E., Zheng, Z., Yengo, L., Lloyd-Jones, L. R., Sidorenko, J., Wu, Y., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Awadalla, P., Battle, A., Beutner, F., Bonder, M. J. J., Boomsma, D., … Yang, J. (2018). Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-04951-w · DOI
  91. Yang, W., Tang, H., Zhang, Y., Tang, X., Zhang, J., Sun, L., Yang, J., Cui, Y., Zhang, L., Hirankarn, N., Cheng, H., Pan, H. F., Gao, J., Lee, T. L., Sheng, Y., Lau, C. S., Li, Y., Chan, T. M., Yin, X., … Lau, Y. L. (2013). Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. American Journal of Human Genetics, 92(1), 41-51. https://doi.org/10.1016/j.ajhg.2012.11.018 · DOI
  92. Yang, Y., Muzny, D. M., Reid, J. G., Bainbridge, M. N., Willis, A., Ward, P. A., Braxton, A., Beuten, J., Xia, F., Niu, Z., Hardison, M., Person, R., Bekheirnia, M. R., Leduc, M. S., Kirby, A., Pham, P., Scull, J., Wang, M., Ding, Y., … Eng, C. M. (2013). Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders. New England Journal of Medicine, 369(16), 1502- 1511. https://doi.org/10.1056/NEJMoa1306555 · DOI
  93. Yu, Y., Bhangale, T. R., Fagerness, J., Ripke, S., Thorleifsson, G., Tan, P. L., Souied, E. H., Richardson, A. J., Merriam, J. E., Buitendijk, G. H. S., Reynolds, R., Raychaudhuri, S., Chin, K. A., Sobrin, L., Evangelou, E., Lee, P. H., Lee, A. Y., Leveziel, N., Zack, D. J., … Seddon, J. M. (2011). Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Human Molecular Genetics, 20(18), 3699-3709. https://doi.org/10.1093/hmg/ddr270 · DOI · Paper page
  94. Yun, T., Li, H., Chang, P.-C., Lin, M., Carroll, A., & McLean, C. (2020). Accurate, scalable cohort variant calls using DeepVariant and GLnexus. BioRxiv, 2020.02.10.942086. https://doi.org/10.1101/2020.02.10.942086 · DOI
  95. Zajickova, K., Vrbikova, J., Canaff, L., Pawelek, P. D., Goltzman, D., & Hendy, G. N. (2007). Identification and functional characterization of a novel mutation in the calcium-sensing receptor gene in familial hypocalciuric hypercalcemia: Modulation of clinical severity by vitamin D status. Journal of Clinical Endocrinology and Metabolism, 92(7), 2616-2623. https://doi.org/10.1210/jc.2007-0123 · DOI
  96. Zhao, W., Rasheed, A., Tikkanen, E., Lee, J. J., Butterworth, A. S., Howson, J. M. M., Assimes, T. L., Chowdhury, R., Orho-Melander, M., Damrauer, S., Small, A., Asma, S., Imamura, M., Yamauch, T., Chambers, J. C., Chen, P., Sapkota, B. R., Shah, N., Jabeen, S., … Saleheen, D. (2017). Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. Nature Genetics, 49(10), 1450-1457. https://doi.org/10.1038/ng.3943 · DOI
  97. Zimmerman, P. A., Buckler-White, A., Alkhatib, G., Spalding, T., Kubofcik, J., Combadiere, C., Weissman, D., Cohen, O., Rubbert, A., Lam, G., Vaccarezza, M., Kennedy, P. E., Kumaraswami, V., Giorgi, J. V., Detels, R., Hunter, J., Chopek, M., Berger, E. A., Fauci, A. S., … Murphy, P. M. (1997). Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: Studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. Molecular Medicine, 3(1), 23- 36. https://doi.org/10.1007/

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Szustakowski, J. D., Balasubramanian, S., Kvikstad, E., Khalid, S., Bronson, P. G., Sasson, A., Wong, E., Liu, D., Wade Davis, J., Haefliger, C., Katrina Loomis, A., Mikkilineni, R., Noh, H. J., Wadhawan, S., Bai, X., Hawes, A., Krasheninina, O., Ulloa, R., Lopez, A. E., Smith, E. N., Waring, J. F., Whelan, C. D., Tsai, E. A., Overton, J. D., Salerno, W. J., Jacob, H., Szalma, S., Runz, H., Hinkle, G., Nioi, P., Petrovski, S., Miller, M. R., Baras, A., Mitnaul, L. J., Reid, J. G., UKB-ESC Research Team, Moiseyenko, O., Rios, C., Saha, S., Abecasis, G., Banerjee, N., Beechert, C., Boutkov, B., Cantor, M., Coppola, G., Economides, A., Eom, G., Forsythe, C., Fuller, E. D., Gu, Z., Habegger, L., Jones, M. B., Lanche, R., Lattari, M., LeBlanc, M., Li, D., Lotta, L. A., Manoochehri, K., Mansfield, A. J., Maxwell, E. K., Mighty, J., Nafde, M., O’Keeffe, S., Orelus, M., Padilla, M. S., Panea, R., Polanco, T., Pradhan, M., Rasool, A., Schleicher, T. D., Sharma, D., Shuldiner, A., Staples, J. C., Van Hout, C. V., Widom, L., Wolf, S. E., John, S., Chen, C.-Y., Sexton, D., Kupelian, V., Marshall, E., Swan, T., Eaton, S., Liu, J. Z., Loomis, S., Jensen, M., Duraisamy, S., Tetrault, J., Merberg, D., Badola, S., Reppell, M., Grundstad, J., Zheng, X., Deaton, A. M., Parker, M. M., Ward, L. D., Flynn-Carroll, A. O., Austin, C., March, R., Pangalos, M. N., Platt, A., Snowden, M., Matakidou, A., Wasilewski, S., Wang, Q., Deevi, S., Carss, K., Smith, K., Sogaard, M., Hu, X., Chen, X., & Ye, Z.
Affiliations
  • Bristol-Myers Squibb (United States) (US)
  • Regeneron (United States) (US)
  • Biogen (United States) (US)
  • AstraZeneca (United Kingdom) (GB)
  • AbbVie (United States) (US)
  • Alnylam Pharmaceuticals (United States) (US)
  • Pfizer (United States) (US)
Corresponding author
Reid, Jeffrey G.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2021-06-28
Volume
53
Issue
7
Pages
942-948
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-021-00885-0
OpenAlex
W3177160312
Semantic Scholar
b2ab640cf37e406b74273a4fa42118ea6561153e
Cited by
401
References
121
Citations by year
2026: 32 · 2025: 66 · 2024: 64 · 2023: 83 · 2022: 107 · 2021: 46 · 2020: 3
FWCI
11.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
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 › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
exome sequencing, UK Biobank, rare coding variants, drug discovery, human genetics, pre-competitive collaboration, public-private partnerships, genetic data access
MeSH terms
Exome Sequencing, Human Genetics, United Kingdom, Humans, Research, Biological Specimen Banks, Genomics, Drug Discovery

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