Audi, Laura

Camacho-Hübner, Cecilia

Dauber, Andrew

Hirschhorn, Joel N

Jorge, Alexander A L

Lindberg, Anders

Ranke, Michael B

Universitat Autònoma de Barcelona

Vedantam, Sailaja

Wajnrajch, Michael P

English

Hirschhorn, Joel N.

Audí, Laura

Ranke, Michael B.

Jorge, Alexander A. L.

Wajnrajch, Michael P.

Diposit Digital de Documents de la UAB

The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 1, e409–e410doi:10.1210/clinem/dgaa735Letter to the Editor ResponseISSN Print 0021-972X ISSN Online 1945-7197Printed in USAhttps://academic.oup.com/jcem   e409© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Letter to the Editor ResponseResponse to Letter to the Editor: “A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness”Joel N. Hirschhorn,1 Andrew Dauber,2 Laura Audi,3 Sailaja Vedantam,1 Michael B. Ranke,4 Alexander  A.L. Jorge,5 Anders Lindberg,6 Cecilia Camacho-Hübner,7 and Michael P. Wajnrajch71Division of Endocrinology, Boston Children’s Hospital, and Program in Medical and Population Genetics, Broad Institute, Harvard Medical School, Boston, Massachusetts 02115; 2Division of Endocrinology, Children’s National Hospital, Washington, DC 20010; 3Department of Pediatrics, Institut de Recerca (VHIR), Hospital Vall d’Hebron, Centre for Biomedical Research on Rare Diseases (CIBERER), Autonomous University, Barcelona, Spain; 4University Children´s Hospital, Paediatric Endocrinology, Tübingen, Germany; 5Unidade de Endocrinologia do Desenvolvimento (LIM42), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil; 6Pfizer, Data Management, Sollentuna Sweden; and 77Pfizer Inc, Rare Disease, New York 10017ORCiD numbers: 0000-0003-4890-0262 (A. Dauber); 0000-0002-8211-9237 (M. P. Wajnrajch).Received: 25 September 2020; Editorial Decision: 8 October 2020; First Published Online: 11 November 2020; Corrected and Typeset: 11 November 2020. Pierre Bougnères correctly points out the limitations of our genome-wide association study (GWAS) of variants affecting growth hormone (GH) response, all of which we raised in our “Discussion,” including a relatively small sample size for GWAS (1). Our main goal was to carry out the first genome-wide search powered to detect variants with moderate to large effects on GH response, and to test some specific hypotheses. Although our study size is small compared with most GWAS of polygenic traits, it was ad-equately powered to detect larger effects that have been seen in other pharmacogenetic settings. Furthermore, the sample sizes needed for replication of individual variants that have themselves been proposed to have large effects, such as the GHRd3 variant, is much smaller than the study sizes needed for comprehensive GWAS discovery, for which effect sizes are more modest and appropriate correction for multiple testing is required. We were also well powered to test the hypothesis that genetically de-termined height influences GH responsiveness, because we effectively examined a single hypothesis with large effect: A  single polygene score of 697 height-associated variants reflects the combined action of all 697 variants (explaining ~16% of the variance in height [2]).In specific reference to the GHRd3 variant, although testing this variant was not the main goal of our study, our re-sults still provide additional information on the likely strength of association with GH responsiveness. The meta-analysis cited by Bougnères (3), which encompassed 1680 children with a wide range of diagnoses and ancestries, reported a 0.075 smaller change in height SD score after 1 year in chil-dren who were homozygous for the more common (minor allele frequency ~0.72) wild-type (WT) allele, and a decrease of –0.159 in the subsample with GH deficiency. In our study, the SD of the change in height SD score was 0.4, meaning that the effect sizes of the WT allele reported in the meta-analysis corresponds to a z score of –0.075/0.4 = –0.188 in all individuals and –0.159/0.4 = –0.40 in individuals with GH deficiency. These effect sizes correspond to approximately 0.9% and approximately 4% of the variance in GH response explained by this one variant. With these effect sizes, we had Downloaded from https://academic.oup.com/jcem/article/106/1/e409/5974059 by guest on 29 April 2021e410  The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 162% and 92% power to achieve a P value of less than .05 in our sample of 614 children, of whom 276 had GH defi-ciency. In our primary analysis, European-ancestry–only ana-lysis, and European-ancestry GH deficiency–only analysis, we actually observed slight trends in the opposite direction (z scores of 0.024, 0.002, and 0.011, with P values of .66, .97, and .89, respectively). None of the 95% CIs around these z scores include the effect sizes reported in the meta-analysis, suggesting that the meta-analysis, at a minimum, has over-estimated the effect of the GHRd3 variant.Of note, in Wassenaar et al (3), the combined meta-analysis P values for association with 2 related measures of GH re-sponsiveness ranged from .03 to .004, and the most signifi-cant of these was driven largely by the study that first reported the association (4). We and others have previously noted that most candidate gene association studies that used a P value of less than .05 as a threshold for declaring significance turned out to be false positives (5-8), which is why the thresholds for declaring significance have since become much more strin-gent (genome-wide significance, typically P less than 5 × 10–8 [9]). We also note that if our study, with a total sample size of more than 600 individuals, were added to the meta-analysis in Wassenaar et al, the combined P value would move even fur-ther away from this threshold of significance. To borrow the metaphor of David and Goliath from Bougnères, a few spe-cial candidate gene association studies hit their target, but most turned out to have gone wide of the mark. Although we cannot definitively say that the association with GHRd3 and GH re-sponsiveness is a false positive, our data strongly indicate that the effect size is not as large as has been previously suggested.Finally, with respect to control of population substruc-ture, we analyzed European-ancestry individuals separately and included principal components of ancestry in our ana-lysis. The paper referenced by Bougnères (10) describes the effects of a subtle signal of population stratification on tests of selection that integrate information across genome-wide sets of summary association statistics for adult height; subtle residual stratification is unlikely to have affected the repli-cation, or lack thereof, of individual variants in our study.AcknowledgmentsFinancial Support: This work was supported by Pfizer.Additional InformationCorrespondence and Reprint Requests: Michael P.  Wajnrajch, MD, MPA, Department of Pediatric Endocrinology, Pfizer Bio-Pharmaceuticals Group, 235 E 42nd St, MS 235-10-01, New York, NY 10017, USA. E-mail: michael.wajnrajch@pfizer.com.Disclosure Summary: J.N.H.  received research support from Pfizer Inc for this study and is on the scientific advisory board of Camp4 Therapeutics; A.D. has received consulting fees from OPKO Biologics, Sandoz, Novo Nordisk, Ipsen, and Pfizer; A.A.L.J.  re-ceived speaker fees from Sandoz and Novo Nordisk; M.B.R.  has received speaker fees from Novo Nordisk, Merck Serono, Sandoz, and Mediagnost. M.P.W.  and C.C.H.  are employees of Pfizer Inc; A.L. was an employee of Pfizer Health AB; and S.V. and L.A. have nothing to declare.References 1. Dauber A, Meng Y, Audi L, et al. A genome-wide pharmacogen-etic study of growth hormone responsiveness. J Clin Endocrinol Metab. 2020;105(10):dgaa443. 2. Wood AR, Esko T, Yang J, et al; Electronic Medical Records and Genomics (eMEMERGEGE) Consortium; MIGen Consortium; PAGEGE Consortium; LifeLines Cohort Study. Defining the role of common variation in the genomic and biological archi-tecture of adult human height. Nat Genet. 2014;46(11): 1173-1186. 3. Wassenaar MJ, Dekkers OM, Pereira AM, et al. Impact of the exon 3-deleted growth hormone (GH) receptor polymorphism on baseline height and the growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD chil-dren with short stature: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2009;94(10):3721-3730. 4. Dos  Santos  C, Essioux  L, Teinturier  C, Tauber  M, Goffin  V, Bougnères P. A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet. 2004;36(7):720-724. 5. Hirschhorn JN, Gajdos ZK. Genome-wide association studies: results from the first few years and potential implications for clinical medicine. Annu Rev Med. 2011;62:11-24. 6. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A com-prehensive review of genetic association studies. Genet Med. 2002;4(2):45-61. 7. Wacholder  S, Chanock  S, Garcia-Closas  M, El  Ghormli  L, Rothman N. Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst. 2004;96(6):434-442. 8. Chanock  SJ, Manolio  T, Boehnke  M, et  al; NCI-NHGRI Working Group on Replication in Association Studies. Replicating genotype-phenotype associations. Nature. 2007;447(7145):655-660. 9. McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide as-sociation studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008;9(5):356-369. 10. Sohail  M, Maier  RM, Ganna  A, et  al. Polygenic adaptation on height is overestimated due to uncorrected stratification in genome-wide association studies. eLife. 2019;8:e39702.Downloaded from https://academic.oup.com/jcem/article/106/1/e409/5974059 by guest on 29 April 2021

Response to Letter to the Editor : "A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness"

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Response to Letter to the Editor : "A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness"

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