Michael J Bray1,2, Lea K Davis2, Eric S Torstenson2, Sarah H Jones3, Todd L Edwards2,3,4,5,6, Digna R Velez Edwards7,8,9,10,11. 1. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. 2. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 3. Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 4. Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 5. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 6. Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 7. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA, digna.r.velez.edwards@vanderbilt.edu. 8. Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee, USA, digna.r.velez.edwards@vanderbilt.edu. 9. Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA, digna.r.velez.edwards@vanderbilt.edu. 10. Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA, digna.r.velez.edwards@vanderbilt.edu. 11. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA, digna.r.velez.edwards@vanderbilt.edu.
Abstract
BACKGROUND: Heritability estimates (including twin and single nucleotide polymorphism [SNP]-based heritability studies) for fibroids have been inconsistent across prior studies ranging between 9 and 69%. These inconsistencies are due to variations in study design and included populations. A major design issue has been lack of imaging confirmation to identify controls, where asymptomatic women without imaging confirmation may be misclassified as controls leading to an attenuation of heritability estimates. To reconcile the differences in prior heritability estimates and the impact of misclassification of controls on heritability, we determined SNP-based heritability and characterized the genetic architecture of pelvic image-confirmed fibroid cases and controls. METHODS: Analyses were performed among women of European American descent using genome-wide SNP data from BioVU, a clinical database composed of DNA linked to de-identified electronic health records. We estimated the genetic variance explained by all SNPs using Genome-Wide Complex Trait Analysis on imputed data. Fibroid cases and controls were identified using a previously reported phenotyping algorithm that required pelvic imaging confirmation. RESULTS: In total, we used 1,067 image-confirmed fibroid cases and 1,042 image-confirmed fibroid controls. The SNP-based heritability estimate for fibroid risk was h2 = 0.33 ± 0.18 (p = 0.040). We investigated the relationship between heritability per chromosome and chromosome length (r2 < 1%), with chromosome 8 explaining the highest proportion of variance for fibroid risk. There was no enrichment for intergenic or genic SNPs for the fibroid SNP-based heritability. Excluding loci previously associated with fibroid risk from genome-wide association study did not attenuate fibroid heritability suggesting that loci associating with fibroid risk are yet to be discovered. CONCLUSIONS: We observed that fibroid SNP-based heritability was higher than the previous estimate using genome-wide SNP data that relied on self-reported outcomes, but within the range of prior twin pair studies. Furthermore, these data support that imprecise phenotyping can significantly affect the ability to estimate heritability using genotype data.
BACKGROUND: Heritability estimates (including twin and single nucleotide polymorphism [SNP]-based heritability studies) for fibroids have been inconsistent across prior studies ranging between 9 and 69%. These inconsistencies are due to variations in study design and included populations. A major design issue has been lack of imaging confirmation to identify controls, where asymptomatic women without imaging confirmation may be misclassified as controls leading to an attenuation of heritability estimates. To reconcile the differences in prior heritability estimates and the impact of misclassification of controls on heritability, we determined SNP-based heritability and characterized the genetic architecture of pelvic image-confirmed fibroid cases and controls. METHODS: Analyses were performed among women of European American descent using genome-wide SNP data from BioVU, a clinical database composed of DNA linked to de-identified electronic health records. We estimated the genetic variance explained by all SNPs using Genome-Wide Complex Trait Analysis on imputed data. Fibroid cases and controls were identified using a previously reported phenotyping algorithm that required pelvic imaging confirmation. RESULTS: In total, we used 1,067 image-confirmed fibroid cases and 1,042 image-confirmed fibroid controls. The SNP-based heritability estimate for fibroid risk was h2 = 0.33 ± 0.18 (p = 0.040). We investigated the relationship between heritability per chromosome and chromosome length (r2 < 1%), with chromosome 8 explaining the highest proportion of variance for fibroid risk. There was no enrichment for intergenic or genic SNPs for the fibroid SNP-based heritability. Excluding loci previously associated with fibroid risk from genome-wide association study did not attenuate fibroid heritability suggesting that loci associating with fibroid risk are yet to be discovered. CONCLUSIONS: We observed that fibroid SNP-based heritability was higher than the previous estimate using genome-wide SNP data that relied on self-reported outcomes, but within the range of prior twin pair studies. Furthermore, these data support that imprecise phenotyping can significantly affect the ability to estimate heritability using genotype data.
Authors: Stacey L Eggert; Karen L Huyck; Priya Somasundaram; Raghava Kavalla; Elizabeth A Stewart; Ake T Lu; Jodie N Painter; Grant W Montgomery; Sarah E Medland; Dale R Nyholt; Susan A Treloar; Krina T Zondervan; Andrew C Heath; Pamela A F Madden; Lynda Rose; Julie E Buring; Paul M Ridker; Daniel I Chasman; Nicholas G Martin; Rita M Cantor; Cynthia C Morton Journal: Am J Hum Genet Date: 2012-10-05 Impact factor: 11.025
Authors: Lea K Davis; Dongmei Yu; Clare L Keenan; Eric R Gamazon; Anuar I Konkashbaev; Eske M Derks; Benjamin M Neale; Jian Yang; S Hong Lee; Patrick Evans; Cathy L Barr; Laura Bellodi; Fortu Benarroch; Gabriel Bedoya Berrio; Oscar J Bienvenu; Michael H Bloch; Rianne M Blom; Ruth D Bruun; Cathy L Budman; Beatriz Camarena; Desmond Campbell; Carolina Cappi; Julio C Cardona Silgado; Danielle C Cath; Maria C Cavallini; Denise A Chavira; Sylvain Chouinard; David V Conti; Edwin H Cook; Vladimir Coric; Bernadette A Cullen; Dieter Deforce; Richard Delorme; Yves Dion; Christopher K Edlund; Karin Egberts; Peter Falkai; Thomas V Fernandez; Patience J Gallagher; Helena Garrido; Daniel Geller; Simon L Girard; Hans J Grabe; Marco A Grados; Benjamin D Greenberg; Varda Gross-Tsur; Stephen Haddad; Gary A Heiman; Sian M J Hemmings; Ana G Hounie; Cornelia Illmann; Joseph Jankovic; Michael A Jenike; James L Kennedy; Robert A King; Barbara Kremeyer; Roger Kurlan; Nuria Lanzagorta; Marion Leboyer; James F Leckman; Leonhard Lennertz; Chunyu Liu; Christine Lochner; Thomas L Lowe; Fabio Macciardi; James T McCracken; Lauren M McGrath; Sandra C Mesa Restrepo; Rainald Moessner; Jubel Morgan; Heike Muller; Dennis L Murphy; Allan L Naarden; William Cornejo Ochoa; Roel A Ophoff; Lisa Osiecki; Andrew J Pakstis; Michele T Pato; Carlos N Pato; John Piacentini; Christopher Pittenger; Yehuda Pollak; Scott L Rauch; Tobias J Renner; Victor I Reus; Margaret A Richter; Mark A Riddle; Mary M Robertson; Roxana Romero; Maria C Rosàrio; David Rosenberg; Guy A Rouleau; Stephan Ruhrmann; Andres Ruiz-Linares; Aline S Sampaio; Jack Samuels; Paul Sandor; Brooke Sheppard; Harvey S Singer; Jan H Smit; Dan J Stein; E Strengman; Jay A Tischfield; Ana V Valencia Duarte; Homero Vallada; Filip Van Nieuwerburgh; Jeremy Veenstra-Vanderweele; Susanne Walitza; Ying Wang; Jens R Wendland; Herman G M Westenberg; Yin Yao Shugart; Euripedes C Miguel; William McMahon; Michael Wagner; Humberto Nicolini; Danielle Posthuma; Gregory L Hanna; Peter Heutink; Damiaan Denys; Paul D Arnold; Ben A Oostra; Gerald Nestadt; Nelson B Freimer; David L Pauls; Naomi R Wray; S Evelyn Stewart; Carol A Mathews; James A Knowles; Nancy J Cox; Jeremiah M Scharf Journal: PLoS Genet Date: 2013-10-24 Impact factor: 5.917
Authors: Jacklyn N Hellwege; Janina M Jeff; Lauren A Wise; C Scott Gallagher; Melissa Wellons; Katherine E Hartmann; Sarah F Jones; Eric S Torstenson; Scott Dickinson; Edward A Ruiz-Narváez; Nadin Rohland; Alexander Allen; David Reich; Arti Tandon; Bogdan Pasaniuc; Nicholas Mancuso; Hae Kyung Im; David A Hinds; Julie R Palmer; Lynn Rosenberg; Joshua C Denny; Dan M Roden; Elizabeth A Stewart; Cynthia C Morton; Eimear E Kenny; Todd L Edwards; Digna R Velez Edwards Journal: Hum Genet Date: 2017-08-23 Impact factor: 5.881