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1. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Author

Ong, Jue-Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Liyanage, Upekha, Dusingize, Jean-Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong-Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A. M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Ong, Jue-Sheng [0000-0002-6062-710X], Dixon-Suen, Suzanne C. [0000-0003-3714-8386], Han, Xikun [0000-0002-3823-7308], Gockel, Ines [0000-0001-7423-713X], Böhmer, Anne [0000-0002-5716-786X], O’Mara, Tracy [0000-0002-5436-3232], Spurdle, Amanda [0000-0003-1337-7897], Law, Matthew H. [0000-0002-4303-8821], Iles, Mark M. [0000-0002-2603-6509], Pharoah, Paul [0000-0001-8494-732X], Zheng, Wei [0000-0003-1226-070X], Thrift, Aaron P. [0000-0002-0084-5308], Olsen, Catherine [0000-0003-4483-1888], Gharahkhani, Puya [0000-0002-4203-5952], Webb, Penelope M. [0000-0003-0733-5930], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
631/67/68, 45/43, article, 692/699/67/2195, 692/4028/67/2324
Abstract

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.

Published
2021
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2. Human loss-of-function variants suggest that partial LRRK2 reduction is not associated with severe disease

Author

Whiffin, N, Armean, IM, Kleinman, A, Marshall, JL, Minikel, EV, Goodrich, JK, Quaife, N, Cole, JB, Wang, Q, Karczewski, KJ, Cummings, BB, Francioli, L, Laricchia, K, Guan, A, Alipanahi, B, Morrison, P, Baptista, MAS, Merchant, KM, Genome Aggregation Database Production Team^, Genome Aggregation Database Consortium, Ware, J, Havulinna, AS, Iliadou, B, Lee, J-J, Nadkarni, GN, Whiteman, C, Daly, M, Esko, T, Hultman, C, Loos, RJF, Milani, L, Palotie, A, Pato, C, Pato, M, Saleheen, D, Sullivan, PF, Alföldi, J, Cannon, P, MacArthur, DG, Wellcome Trust, Imper, and Rosetrees Trust

Subjects
Immunology, 11 Medical and Health Sciences, nervous system diseases
Abstract

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation, and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well-characterized in humans. Here we systematically analyse pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome sequenced individuals from the UK Biobank, and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with prior work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.

Published
2020

3. Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases

Author

An, Jiyuan, Gharahkhani, Puya, Law, Matthew H., Ong, Jue-Sheng, Han, Xikun, Olsen, Catherine M., Neale, Rachel E., Lai, John, Vaughan, Tom L., Gockel, Ines, Thieme, René, Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, Whiteman, David C., MacGregor, Stuart, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Murray, Liam J., Reid, Brian J., Chow, Wong-Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A. M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Gharahkhani, Puya [0000-0002-4203-5952], Law, Matthew H. [0000-0002-4303-8821], Ong, Jue-Sheng [0000-0002-6062-710X], Han, Xikun [0000-0002-3823-7308], Olsen, Catherine M. [0000-0003-4483-1888], Böhmer, Anne C. [0000-0002-5716-786X], Fitzgerald, Rebecca C. [0000-0002-3434-3568], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository

Subjects
631/67/1504/1477, 631/208/205/2138, 45/43, article, 38/39, 631/208/68, 692/699/1503/1476/196, health care economics and organizations, humanities, digestive system diseases
Abstract

Funder: The Swedish Esophageal Cancer Study was funded by grants (R01 CA57947-03) from the National Cancer Institute he California Tobacco Related Research Program (3RT-0122; and; 10RT-0251) Marit Peterson Fund for Melanoma Research. CIDR is supported by contract HHSN268200782096C, Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions.

Published
2019

4. Overlapping genetic architecture between Parkinson disease and melanoma

Author

Dube, U., Ibanez, L., Budde, J. P., Benitez, B. A., Davis, A. A., Harari, O., Iles, M. M., Law, M. H., Brown, K. M., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., Mccreight, J. C., Mcintyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A. M., Pitts, S. J., Sathirapongsasuti, J. F., Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Bishop, D. T., Lee, J. E., Brossard, M., Martin, N. G., Moses, E. K., Song, F., Barrett, J. H., Kumar, R., Easton, D. F., Pharoah, P. D., Swerdlow, A. J., Kypreou, K. P., Taylor, J. C., Harland, M., Randerson-Moor, J., Akslen, L. A., Andresen, P. A., Avril, M. F., Azizi, E., Scarra, G. B., Debniak, T., Duffy, D. L., Elder, D. E., Fang, S., Friedman, E., Galan, P., Ghiorzo, P., Gillanders, E. M., Goldstein, A. M., Gruis, N. A., Hansson, J., Helsing, P., Hocevar, M., Hoiom, V., Ingvar, C., Kanetsky, P. A., Chen, W. V., Landi, M. T., Lang, J., Lathrop, G. M., Lubinski, J., Mackie, R. M., Mann, G. J., Molven, A., Montgomery, G. W., Novakovic, S., Olsson, H., Puig, S., Puig-Butille, J. A., Wu, W., Qureshi, A. A., Radford-Smith, G. L., van der Stoep, N., van Doorn, R., Whiteman, D. C., Craig, J. E., Schadendorf, E., Simms, L. A., Burdon, K. P., Nyholt, D. R., Pooley, K. A., Orr, N., Stratigos, A. J., Cust, A. E., Ward, S. V., Hayward, N. K., Han, J., Schulze, H. J., Dunning, A. M., Bishop, J. A., Demenais, F., Amos, C. I., Macgregor, S., and Cruchaga, C.

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Genetic correlation, Multifactorial Inheritance, Skin Neoplasms, Medizin, TWAS, Disease, Melanoma, Parkinson disease, Polygenic, Shared genetic architecture, Pathology and Forensic Medicine, Correlation, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, Gene expression, Medicine, Humans, Gene, business.industry, Parkinson Disease, medicine.disease, Genetic architecture, 030104 developmental biology, Case-Control Studies, Cutaneous melanoma, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 x 10(-06)) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 x 10(-04)) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.

Published
2019

5. Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms

Author

Jones, SE, Lane, JM, Wood, AR, van Hees, VT, Tyrrell, J, Beaumont, RN, Jeffries, AR, Dashti, HS, Hillsdon, M, Ruth, KS, Tuke, MA, Yaghootkar, H, Sharp, SA, Jie, YJ, Thompson, WD, Harrison, JW, Dawes, A, Byrne, EM, Tiemeier, Henning, Allebrandt, KV, Bowden, J, Ray, DW, Freathy, RM, Murray, A, Mazzotti, DR, Gehrman, PR, Lawlor, DA, Frayling, TM, Rutter, MK, Hinds, DA, Saxena, R, Weedon, MN, Agee, M, Alipanahi, B, Auton, A, Bell, RK, Bryc, K, Elson, SL, Fontanillas, P, Furlotte, NA, Huber, KE, Kleinman, A, Litterman, NK, McCreight, JC, McIntyre, MH, Mountain, JL, Noblin, ES, Northover, CAM, Pitts, SJ, Sathirapongsasuti, JF, Sazonova, OV, Shelton, JF, Shringarpure, S, Tian, C, Tung, JY, Vacic, V, Wilson, CH, Epidemiology, and Psychiatry

Published
2019

6. An atlas of genetic influences on osteoporosis in humans and mice

Author

Morris, JA, Kemp, JP, Youlten, SE, Laurent, L, Logan, JG, Chai, RC, Vulpescu, NA, Forgetta, V, Kleinman, A, Mohanty, ST, Sergio, CM, Quinn, J, Nguyen-Yamamoto, L, Luco, A-L, Vijay, J, Simon, M-M, Pramatarova, A, Medina-Gomez, C, Trajanoska, K, Ghirardello, EJ, Butterfield, NC, Curry, KF, Leitch, VD, Sparkes, PC, Adoum, A-T, Mannan, NS, Komla-Ebri, DSK, Pollard, AS, Dewhurst, HF, Hassall, TAD, Beltejar, M-JG, Agee, M, Alipanahi, B, Auton, A, Bell, RK, Bryc, K, Elson, SL, Fontanillas, P, Furlotte, NA, McCreight, JC, Huber, KE, Litterman, NK, McIntyre, MH, Mountain, JL, Noblin, ES, Northover, CAM, Pitts, SJ, Sathirapongsasuti, JF, Sazonova, OV, Shelton, JF, Shringarpure, S, Tian, C, Tung, JY, Vacic, V, Wilson, CH, Adams, DJ, Vaillancourt, SM, Kaptoge, S, Baldock, P, Cooper, C, Reeve, J, Ntzani, EE, Evangelou, E, Ohlsson, C, Karasik, D, Rivadeneira, F, Kiel, DP, Tobias, JH, Gregson, CL, Harvey, NC, Grundberg, E, Goltzman, D, Lelliott, CJ, Hinds, DA, Ackert-Bicknell, CL, Hsu, Y-H, Maurano, MT, Croucher, PI, Williams, GR, Bassett, JHD, Evans, DM, Richards, JB, Wellcome Trust, and Internal Medicine

Subjects
CHROMATIN, Male, Bone density, Osteoporosis, Genome-wide association study, Fractures, Bone, Mice, 0302 clinical medicine, Bone Density, CALCANEUS, 11 Medical and Health Sciences, Bone mineral, Genetics & Heredity, Mice, Knockout, 0303 health sciences, HERITABILITY, Middle Aged, Phenotype, 3. Good health, Female, BONE-MINERAL DENSITY, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 23andMe Research Team, Article, 03 medical and health sciences, FRACTURES, Internal medicine, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, HEEL, 030304 developmental biology, Aged, Science & Technology, HIP, Bone fracture, Odds ratio, 06 Biological Sciences, medicine.disease, Endocrinology, QUANTITATIVE ULTRASOUND, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract

Osteoporosis is a common debilitating chronic disease diagnosed primarily using bone mineral density (BMD). We undertook a comprehensive assessment of human genetic determinants of bone density in 426,824 individuals, identifying a total of 518 genome-wide significant loci, (301 novel), explaining 20% of the total variance in BMD—as estimated by heel quantitative ultrasound (eBMD). Next, meta-analysis identified 13 bone fracture loci in ~1.2M individuals, which were also associated with BMD. We then identified target genes from cell-specific genomic landscape features, including chromatin conformation and accessible chromatin sites, that were strongly enriched for genes known to influence bone density and strength (maximum odds ratio = 58, P = 10-75). We next performed rapid throughput skeletal phenotyping of 126 knockout mice lacking eBMD Target Genes and showed that these mice had an increased frequency of abnormal skeletal phenotypes compared to 526 unselected lines (P < 0.0001). In-depth analysis of one such Target Gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This comprehensive human and murine genetic atlas provides empirical evidence testing how to link associated SNPs to causal genes, offers new insights into osteoporosis pathophysiology and highlights opportunities for drug development.

Published
2018

7. Genome-Wide Mutation Landscape in Autism Spectrum Disorder

Author

Ryan Yuen, Merico, D., Cao, H., Alipanahi, B., Thiruvahindrapuram, B., Pellecchia, G., Tong, X., Cao, D., Sun, Y., Li, M., Chen, W., Jin, X., Nalpathamkalam, T., Bookman, M., Bingham, J., Gross, S., Loy, D., Walker, S., Howe, J. L., Pletcher, M., Marshall, C. R., Szatmari, P., Glazer, D., Frey, B. J., Ring, R. H., and Scherer, S. W.

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