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Admixture mapping identifies African and Amerindigenous local ancestry loci associated with fetal growth

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Abstract

Fetal growth is an important determinant of cardiometabolic disease risk during childhood and adulthood. The genetic architecture of fetal growth remains largely understudied in ancestrally diverse populations. We conducted genome-wide admixture mapping scan and analysis of genetic ancestry among Hispanic American, African American, European American, and Asian American pregnant women to identify genetic loci associated with fetal growth measures across 13–40 weeks gestation. Fetal growth measures were associated with genome-wide average African, European, Amerindigenous and East Asian ancestry proportions (P ranged from10−3 to 4.8 × 10–2). Admixture mapping analysis identified ten African ancestry loci and three Amerindigenous ancestry loci significantly associated with fetal growth measures at Bonferroni-corrected levels of significance (P ranged from 2.18 × 10–8 to 3.71 × 10–6). At the chr2q23.3–24.2 locus in which higher African ancestry was associated with long bone (femur and humerus) lengths, the T allele of rs13030825 (GALNT13) was associated with longer humerus length in African Americans (β = 0.44, P = 6.25 × 10–6 at week 27; β = 0.39, P = 7.72 × 10–5 at week 40). The rs13030825 SNP accounted for most of the admixture association at the chr2q23.3–24.2 locus and has substantial allele frequency difference between African and European reference samples (FST = 0.55, P = 0.03). Regulatory annotation shows that rs13030825 overlaps with the serum response factor (SRF) transcription factor previously implicated in postnatal bone development of mice. Overall, we identified ancestry-related maternal genetic loci that influence fetal growth, shedding light on molecular pathways that regulate fetal growth and potential effects on health across the lifespan.

Clinical trials registration ClinicalTrials.gov, NCT00912132.

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Data availability

The genotype data underlying the findings reported in this study are available for interested researchers upon request through the NICHD Division of Intramural Population Health Research Biospecimen Repository Access and Data Sharing platform.

References

  • Alexander DH, Lange K (2011) Enhancements to the ADMIXTURE algorithm for individual ancestry estimation. BMC Bioinformatics 12:246. https://doi.org/10.1186/1471-2105-12-246

    Article  PubMed  PubMed Central  Google Scholar 

  • Alexander DH, Novembre J, Lange K (2009) Fast model-based estimation of ancestry in unrelated individuals. Genome Res 19:1655–1664. https://doi.org/10.1101/gr.094052.109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andersson O, Korach-Andre M, Reissmann E, Ibanez CF, Bertolino P (2008) Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity. Proc Natl Acad Sci U S A 105:7252–7256. https://doi.org/10.1073/pnas.0800272105

    Article  PubMed  PubMed Central  Google Scholar 

  • Asgari S, Luo Y, Akbari A, Belbin GM, Li X, Harris DN, Selig M, Bartell E, Calderon R, Slowikowski K, Contreras C, Yataco R, Galea JT, Jimenez J, Coit JM, Farronay C, Nazarian RM, O’Connor TD, Dietz HC, Hirschhorn JN, Guio H, Lecca L, Kenny EE, Freeman EE, Murray MB, Raychaudhuri S (2020) A positively selected FBN1 missense variant reduces height in Peruvian individuals. Nature 582:234–239. https://doi.org/10.1038/s41586-020-2302-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Astone NM, Misra D, Lynch C (2007) The effect of maternal socio-economic status throughout the lifespan on infant birthweight. Paediatr Perinat Epidemiol 21:310–318. https://doi.org/10.1111/j.1365-3016.2007.00821.x

    Article  PubMed  Google Scholar 

  • Baker JL, Rotimi CN, Shriner D (2017) Human ancestry correlates with language and reveals that race is not an objective genomic classifier. Sci Rep 7:1572. https://doi.org/10.1038/s41598-017-01837-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barker DJ, Godfrey KM, Osmond C, Bull A (1992) The relation of fetal length, ponderal index and head circumference to blood pressure and the risk of hypertension in adult life. Paediatr Perinat Epidemiol 6:35–44

    Article  CAS  PubMed  Google Scholar 

  • Beaumont RN, Warrington NM, Cavadino A, Tyrrell J, Nodzenski M, Horikoshi M, Geller F, Myhre R, Richmond RC, Paternoster L, Bradfield JP, Kreiner-Moller E, Huikari V, Metrustry S, Lunetta KL, Painter JN, Hottenga JJ, Allard C, Barton SJ, Espinosa A, Marsh JA, Potter C, Zhang G, Ang W, Berry DJ, Bouchard L, Das S, Early Growth Genetics C, Hakonarson H, Heikkinen J, Helgeland O, Hocher B, Hofman A, Inskip HM, Jones SE, Kogevinas M, Lind PA, Marullo L, Medland SE, Murray A, Murray JC, Njolstad PR, Nohr EA, Reichetzeder C, Ring SM, Ruth KS, Santa-Marina L, Scholtens DM, Sebert S, Sengpiel V, Tuke MA, Vaudel M, Weedon MN, Willemsen G, Wood AR, Yaghootkar H, Muglia LJ, Bartels M, Relton CL, Pennell CE, Chatzi L, Estivill X, Holloway JW, Boomsma DI, Montgomery GW, Murabito JM, Spector TD, Power C, Jarvelin MR, Bisgaard H, Grant SFA, Sorensen TIA, Jaddoe VW, Jacobsson B, Melbye M, McCarthy MI, Hattersley AT, Hayes MG, Frayling TM, Hivert MF, Felix JF, Hypponen E, Lowe WL Jr, Evans DM, Lawlor DA, Feenstra B, Freathy RM (2018) Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. Hum Mol Genet 27:742–756. https://doi.org/10.1093/hmg/ddx429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bergstrom A, McCarthy SA, Hui R, Almarri MA, Ayub Q, Danecek P, Chen Y, Felkel S, Hallast P, Kamm J, Blanche H, Deleuze JF, Cann H, Mallick S, Reich D, Sandhu MS, Skoglund P, Scally A, Xue Y, Durbin R, Tyler-Smith C (2020) Insights into human genetic variation and population history from 929 diverse genomes. Science. https://doi.org/10.1126/science.aay5012

    Article  PubMed  PubMed Central  Google Scholar 

  • Bertolino P, Holmberg R, Reissmann E, Andersson O, Berggren PO, Ibanez CF (2008) Activin B receptor ALK7 is a negative regulator of pancreatic beta-cell function. Proc Natl Acad Sci U S A 105:7246–7251. https://doi.org/10.1073/pnas.0801285105

    Article  PubMed  PubMed Central  Google Scholar 

  • Bonilla C, Parra EJ, Pfaff CL, Dios S, Marshall JA, Hamman RF, Ferrell RE, Hoggart CL, McKeigue PM, Shriver MD (2004) Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping. Ann Hum Genet 68:139–153. https://doi.org/10.1046/j.1529-8817.2003.00084.x

    Article  CAS  PubMed  Google Scholar 

  • Bryc K, Durand EY, Macpherson JM, Reich D, Mountain JL (2015) The genetic ancestry of African Americans, Latinos, and European Americans across the United States. Am J Hum Genet 96:37–53. https://doi.org/10.1016/j.ajhg.2014.11.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buck Louis GM, Grewal J, Albert PS, Sciscione A, Wing DA, Grobman WA, Newman RB, Wapner R, D’Alton ME, Skupski D, Nageotte MP, Ranzini AC, Owen J, Chien EK, Craigo S, Hediger ML, Kim S, Zhang C, Grantz KL (2015) Racial/ethnic standards for fetal growth: the NICHD Fetal Growth Studies. Am J Obstet Gynecol 213:449e1-449e41. https://doi.org/10.1016/j.ajog.2015.08.032

    Article  Google Scholar 

  • Burris HH, Hacker MR (2017) Birth outcome racial disparities: a result of intersecting social and environmental factors. Semin Perinatol 41:360–366. https://doi.org/10.1053/j.semperi.2017.07.002

    Article  PubMed  PubMed Central  Google Scholar 

  • Chang SC, O’Brien KO, Nathanson MS, Caulfield LE, Mancini J, Witter FR (2003) Fetal femur length is influenced by maternal dairy intake in pregnant African American adolescents. Am J Clin Nutr 77:1248–1254. https://doi.org/10.1093/ajcn/77.5.1248

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Yuan K, Mao X, Miano JM, Wu H, Chen Y (2012) Serum response factor regulates bone formation via IGF-1 and Runx2 signals. J Bone Miner Res 27:1659–1668. https://doi.org/10.1002/jbmr.1607

    Article  CAS  PubMed  Google Scholar 

  • Cooper RS, Nadkarni GN, Ogedegbe G (2018) Race, ancestry, and reporting in medical journals. JAMA. https://doi.org/10.1001/jama.2018.10960

    Article  PubMed  PubMed Central  Google Scholar 

  • Eaves LJ, Pourcain BS, Smith GD, York TP, Evans DM (2014) Resolving the effects of maternal and offspring genotype on dyadic outcomes in genome wide complex trait analysis (“M-GCTA”). Behav Genet 44:445–455. https://doi.org/10.1007/s10519-014-9666-6

    Article  PubMed  PubMed Central  Google Scholar 

  • Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, Berry DJ, Warrington NM, Widen E, Hottenga JJ, Kaakinen M, Lange LA, Bradfield JP, Kerkhof M, Marsh JA, Magi R, Chen CM, Lyon HN, Kirin M, Adair LS, Aulchenko YS, Bennett AJ, Borja JB, Bouatia-Naji N, Charoen P, Coin LJ, Cousminer DL, de Geus EJ, Deloukas P, Elliott P, Evans DM, Froguel P, Genetic Investigation of ATC, Glaser B, Groves CJ, Hartikainen AL, Hassanali N, Hirschhorn JN, Hofman A, Holly JM, Hypponen E, Kanoni S, Knight BA, Laitinen J, Lindgren CM, Meta-Analyses of G, Insulin-related traits C, McArdle WL, O’Reilly PF, Pennell CE, Postma DS, Pouta A, Ramasamy A, Rayner NW, Ring SM, Rivadeneira F, Shields BM, Strachan DP, Surakka I, Taanila A, Tiesler C, Uitterlinden AG, van Duijn CM, Wellcome Trust Case Control C, Wijga AH, Willemsen G, Zhang H, Zhao J, Wilson JF, Steegers EA, Hattersley AT, Eriksson JG, Peltonen L, Mohlke KL, Grant SF, Hakonarson H, Koppelman GH, Dedoussis GV, Heinrich J, Gillman MW, Palmer LJ, Frayling TM, Boomsma DI, Davey Smith G, Power C, Jaddoe VW, Jarvelin MR, Early Growth Genetics C, McCarthy MI (2010) Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet 42:430–435. https://doi.org/10.1038/ng.567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gaskins RB, LaGasse LL, Liu J, Shankaran S, Lester BM, Bada HS, Bauer CR, Das A, Higgins RD, Roberts M (2010) Small for gestational age and higher birth weight predict childhood obesity in preterm infants. Am J Perinatol 27:721–730. https://doi.org/10.1055/s-0030-1253555

    Article  PubMed  PubMed Central  Google Scholar 

  • Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR (2015) A global reference for human genetic variation. Nature 526:68–74. https://doi.org/10.1038/nature15393

    Article  CAS  Google Scholar 

  • Geronimus AT (1996) Black/white differences in the relationship of maternal age to birthweight: a population-based test of the weathering hypothesis. Soc Sci Med 42:589–597

    Article  CAS  PubMed  Google Scholar 

  • Godfrey KM, Barker DJ (2000) Fetal nutrition and adult disease. Am J Clin Nutr 71:1344S-S1352. https://doi.org/10.1093/ajcn/71.5.1344s

    Article  CAS  PubMed  Google Scholar 

  • Grewal J, Grantz KL, Zhang C, Sciscione A, Wing DA, Grobman WA, Newman RB, Wapner R, D’Alton ME, Skupski D, Nageotte MP, Ranzini AC, Owen J, Chien EK, Craigo S, Albert PS, Kim S, Hediger ML, Buck Louis GM (2018) Cohort profile: NICHD fetal growth studies-singletons and twins. Int J Epidemiol 47:25–25l. https://doi.org/10.1093/ije/dyx161

    Article  PubMed  Google Scholar 

  • Hadlock FP, Harrist RB, Sharman RS, Deter RL, Park SK (1985) Estimation of fetal weight with the use of head, body, and femur measurements–a prospective study. Am J Obstet Gynecol 151:333–337

    Article  CAS  PubMed  Google Scholar 

  • Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD (1991) Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303:1019–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harper LM, Gray D, Dicke J, Stamilio DM, Macones GA, Odibo AO (2010) Do race-specific definitions of short long bones improve the detection of down syndrome on second-trimester genetic sonograms? J Ultrasound Med 29:231–235

    Article  PubMed  Google Scholar 

  • Hediger ML, Fuchs KM, Grantz KL, Grewal J, Kim S, Gore-Langton RE, Buck Louis GM, D’Alton ME, Albert PS (2016) Ultrasound quality assurance for singletons in the national institute of child health and human development fetal growth studies. J Ultrasound Med 35:1725–1733. https://doi.org/10.7863/ultra.15.09087

    Article  PubMed  PubMed Central  Google Scholar 

  • Horikoshi M, Yaghootkar H, Mook-Kanamori DO, Sovio U, Taal HR, Hennig BJ, Bradfield JP, St Pourcain B, Evans DM, Charoen P, Kaakinen M, Cousminer DL, Lehtimaki T, Kreiner-Moller E, Warrington NM, Bustamante M, Feenstra B, Berry DJ, Thiering E, Pfab T, Barton SJ, Shields BM, Kerkhof M, van Leeuwen EM, Fulford AJ, Kutalik Z, Zhao JH, den Hoed M, Mahajan A, Lindi V, Goh LK, Hottenga JJ, Wu Y, Raitakari OT, Harder MN, Meirhaeghe A, Ntalla I, Salem RM, Jameson KA, Zhou K, Monies DM, Lagou V, Kirin M, Heikkinen J, Adair LS, Alkuraya FS, Al-Odaib A, Amouyel P, Andersson EA, Bennett AJ, Blakemore AI, Buxton JL, Dallongeville J, Das S, de Geus EJ, Estivill X, Flexeder C, Froguel P, Geller F, Godfrey KM, Gottrand F, Groves CJ, Hansen T, Hirschhorn JN, Hofman A, Hollegaard MV, Hougaard DM, Hypponen E, Inskip HM, Isaacs A, Jorgensen T, Kanaka-Gantenbein C, Kemp JP, Kiess W, Kilpelainen TO, Klopp N, Knight BA, Kuzawa CW, McMahon G, Newnham JP, Niinikoski H, Oostra BA, Pedersen L, Postma DS, Ring SM, Rivadeneira F, Robertson NR, Sebert S, Simell O, Slowinski T, Tiesler CM, Tonjes A, Vaag A, Viikari JS, Vink JM, Vissing NH, Wareham NJ, Willemsen G, Witte DR, Zhang H et al (2013) New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism. Nat Genet 45:76–82. https://doi.org/10.1038/ng.2477

    Article  CAS  PubMed  Google Scholar 

  • Horikoshi M, Beaumont RN, Day FR, Warrington NM, Kooijman MN, Fernandez-Tajes J, Feenstra B, van Zuydam NR, Gaulton KJ, Grarup N, Bradfield JP, Strachan DP, Li-Gao R, Ahluwalia TS, Kreiner E, Rueedi R, Lyytikainen LP, Cousminer DL, Wu Y, Thiering E, Wang CA, Have CT, Hottenga JJ, Vilor-Tejedor N, Joshi PK, Boh ETH, Ntalla I, Pitkanen N, Mahajan A, van Leeuwen EM, Joro R, Lagou V, Nodzenski M, Diver LA, Zondervan KT, Bustamante M, Marques-Vidal P, Mercader JM, Bennett AJ, Rahmioglu N, Nyholt DR, Ma RCW, Tam CHT, Tam WH, Group CCHW, Ganesh SK, van Rooij FJ, Jones SE, Loh PR, Ruth KS, Tuke MA, Tyrrell J, Wood AR, Yaghootkar H, Scholtens DM, Paternoster L, Prokopenko I, Kovacs P, Atalay M, Willems SM, Panoutsopoulou K, Wang X, Carstensen L, Geller F, Schraut KE, Murcia M, van Beijsterveldt CE, Willemsen G, Appel EVR, Fonvig CE, Trier C, Tiesler CM, Standl M, Kutalik Z, Bonas-Guarch S, Hougaard DM, Sanchez F, Torrents D, Waage J, Hollegaard MV, de Haan HG, Rosendaal FR, Medina-Gomez C, Ring SM, Hemani G, McMahon G, Robertson NR, Groves CJ, Langenberg C, Luan J, Scott RA, Zhao JH, Mentch FD, MacKenzie SM, Reynolds RM, Early Growth Genetics C, Lowe WL Jr., Tonjes A, Stumvoll M, Lindi V, et al. (2016) Genome-wide associations for birth weight and correlations with adult disease. Nature 538: 248–252. https://doi.org/10.1038/nature19806

  • Kiserud T, Benachi A, Hecher K, Perez RG, Carvalho J, Piaggio G, Platt LD (2018) The World Health Organization fetal growth charts: concept, findings, interpretation, and application. Am J Obstet Gynecol 218:S619–S629. https://doi.org/10.1016/j.ajog.2017.12.010

    Article  PubMed  Google Scholar 

  • Kovac CM, Brown JA, Apodaca CC, Napolitano PG, Pierce B, Patience T, Hume RF Jr, Calhoun BC (2002) Maternal ethnicity and variation of fetal femur length calculations when screening for Down syndrome. J Ultrasound Med 21:719–22

    Article  PubMed  Google Scholar 

  • Krieger N, Sidney S, Coakley E (1998) Racial discrimination and skin color in the CARDIA study: implications for public health research. Coronary artery risk development in young adults. Am J Public Health 88:1308–1313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li JZ, Absher DM, Tang H, Southwick AM, Casto AM, Ramachandran S, Cann HM, Barsh GS, Feldman M, Cavalli-Sforza LL, Myers RM (2008) Worldwide human relationships inferred from genome-wide patterns of variation. Science 319:1100–1104. https://doi.org/10.1126/science.1153717

    Article  CAS  PubMed  Google Scholar 

  • Maples BK, Gravel S, Kenny EE, Bustamante CD (2013) RFMix: a discriminative modeling approach for rapid and robust local-ancestry inference. Am J Hum Genet 93:278–288. https://doi.org/10.1016/j.ajhg.2013.06.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin AR, Kanai M, Kamatani Y, Okada Y, Neale BM, Daly MJ (2019) Clinical use of current polygenic risk scores may exacerbate health disparities. Nat Genet 51:584–591. https://doi.org/10.1038/s41588-019-0379-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miano JM (2003) Serum response factor: toggling between disparate programs of gene expression. J Mol Cell Cardiol 35:577–593. https://doi.org/10.1016/s0022-2828(03)00110-x

    Article  CAS  PubMed  Google Scholar 

  • Mikkola K, Ritari N, Tommiska V, Salokorpi T, Lehtonen L, Tammela O, Paakkonen L, Olsen P, Korkman M, Fellman V (2005) Neurodevelopmental outcome at 5 years of age of a national cohort of extremely low birth weight infants who were born in 1996–1997. Pediatrics 116:1391–1400. https://doi.org/10.1542/peds.2005-0171

    Article  PubMed  Google Scholar 

  • Mutambudzi M, Meyer JD, Reisine S, Warren N (2017) A review of recent literature on materialist and psychosocial models for racial and ethnic disparities in birth outcomes in the US, 2000–2014. Ethn Health 22:311–332. https://doi.org/10.1080/13557858.2016.1247150

    Article  PubMed  Google Scholar 

  • Ochs-Balcom HM, Shaw H, Preus L, Palmer JR, Haddad SA, Rosenberg L, Ruiz-Narvaez EA (2018) Admixture mapping and fine-mapping of birth weight loci in the Black Women’s Health Study. Hum Genet 137:535–542. https://doi.org/10.1007/s00439-018-1908-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parra EJ, Kittles RA, Shriver MD (2004) Implications of correlations between skin color and genetic ancestry for biomedical research. Nat Genet 36:S54-60. https://doi.org/10.1038/ng1440

    Article  CAS  PubMed  Google Scholar 

  • Pinheiro J, Bates D (2000) Mixed-effects models in S and S-PLUS, 1st edn. Springer-Verlag New York, New York

    Book  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575. https://doi.org/10.1086/519795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reiner AP, Ziv E, Lind DL, Nievergelt CM, Schork NJ, Cummings SR, Phong A, Burchard EG, Harris TB, Psaty BM, Kwok PY (2005) Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study. Am J Hum Genet 76:463–477. https://doi.org/10.1086/428654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roland MC, Friis CM, Voldner N, Godang K, Bollerslev J, Haugen G, Henriksen T (2012) Fetal growth versus birthweight: the role of placenta versus other determinants. PLoS ONE 7:e39324. https://doi.org/10.1371/journal.pone.0039324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossen LM, Schoendorf KC (2014) Trends in racial and ethnic disparities in infant mortality rates in the United States, 1989–2006. Am J Public Health 104:1549–1556. https://doi.org/10.2105/AJPH.2013.301272

    Article  PubMed  PubMed Central  Google Scholar 

  • Ruiz-Linares A, Adhikari K, Acuna-Alonzo V, Quinto-Sanchez M, Jaramillo C, Arias W, Fuentes M, Pizarro M, Everardo P, de Avila F, Gomez-Valdes J, Leon-Mimila P, Hunemeier T, Ramallo V, Silva de Cerqueira CC, Burley MW, Konca E, de Oliveira MZ, Veronez MR, Rubio-Codina M, Attanasio O, Gibbon S, Ray N, Gallo C, Poletti G, Rosique J, Schuler-Faccini L, Salzano FM, Bortolini MC, Canizales-Quinteros S, Rothhammer F, Bedoya G, Balding D, Gonzalez-Jose R (2014) Admixture in Latin America: geographic structure, phenotypic diversity and self-perception of ancestry based on 7,342 individuals. PLoS Genet 10:e1004572. https://doi.org/10.1371/journal.pgen.1004572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shipp TD, Bromley B, Mascola M, Benacerraf B (2001) Variation in fetal femur length with respect to maternal race. J Ultrasound Med 20:141–144

    Article  CAS  PubMed  Google Scholar 

  • Shriner D (2017) Overview of admixture mapping. Curr Protoc Hum Genet 94:1231–1238. https://doi.org/10.1002/cphg.44

    Article  Google Scholar 

  • Shriner D, Tekola-Ayele F, Adeyemo A, Rotimi CN (2014) Genome-wide genotype and sequence-based reconstruction of the 140,000 year history of modern human ancestry. Sci Rep 4:6055. https://doi.org/10.1038/srep06055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tekola-Ayele F, Workalemahu T, Amare AT (2018) High burden of birthweight-lowering genetic variants in Africans and Asians. BMC Med 16:70. https://doi.org/10.1186/s12916-018-1061-3

    Article  PubMed  PubMed Central  Google Scholar 

  • Tekola-Ayele F, Zhang C, Wu J, Grantz KL, Rahman ML, Shrestha D, Ouidir M, Workalemahu T, Tsai MY (2020) Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy. PLoS Genet 16:e1008747. https://doi.org/10.1371/journal.pgen.1008747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934. https://doi.org/10.1093/nar/gkr917

    Article  CAS  PubMed  Google Scholar 

  • Warrington NM, Beaumont RN, Horikoshi M, Day FR, Helgeland O, Laurin C, Bacelis J, Peng S, Hao K, Feenstra B, Wood AR, Mahajan A, Tyrrell J, Robertson NR, Rayner NW, Qiao Z, Moen GH, Vaudel M, Marsit CJ, Chen J, Nodzenski M, Schnurr TM, Zafarmand MH, Bradfield JP, Grarup N, Kooijman MN, Li-Gao R, Geller F, Ahluwalia TS, Paternoster L, Rueedi R, Huikari V, Hottenga JJ, Lyytikainen LP, Cavadino A, Metrustry S, Cousminer DL, Wu Y, Thiering E, Wang CA, Have CT, Vilor-Tejedor N, Joshi PK, Painter JN, Ntalla I, Myhre R, Pitkanen N, van Leeuwen EM, Joro R, Lagou V, Richmond RC, Espinosa A, Barton SJ, Inskip HM, Holloway JW, Santa-Marina L, Estivill X, Ang W, Marsh JA, Reichetzeder C, Marullo L, Hocher B, Lunetta KL, Murabito JM, Relton CL, Kogevinas M, Chatzi L, Allard C, Bouchard L, Hivert MF, Zhang G, Muglia LJ, Heikkinen J, Consortium EGG, Morgen CS, van Kampen AHC, van Schaik BDC, Mentch FD, Langenberg C, Luan J, Scott RA, Zhao JH, Hemani G, Ring SM, Bennett AJ, Gaulton KJ, Fernandez-Tajes J, van Zuydam NR, Medina-Gomez C, de Haan HG, Rosendaal FR, Kutalik Z, Marques-Vidal P, Das S, Willemsen G, Mbarek H, Muller-Nurasyid M, Standl M, Appel EVR, Fonvig CE, et al. (2019) Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nat Genet 51: 804–814. https://doi.org/10.1038/s41588-019-0403-1

  • Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, Klemm A, Flicek P, Manolio T, Hindorff L, Parkinson H (2014) The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 42:D1001–D1006. https://doi.org/10.1093/nar/gkt1229

    Article  CAS  PubMed  Google Scholar 

  • Workalemahu T, Grantz KL, Grewal J, Zhang C, Louis GMB, Tekola-Ayele F (2018) Genetic and environmental influences on fetal growth vary during sensitive periods in pregnancy. Sci Rep 8:7274. https://doi.org/10.1038/s41598-018-25706-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge the research teams at all participating clinical centers for the NICHD Fetal Growth Studies, including Christina Care Health Systems, Columbia University, Fountain Valley Hospital, California, Long Beach Memorial Medical Center, New York Hospital, Queens, Northwestern University, University of Alabama at Birmingham, University of California, Irvine, Medical University of South Carolina, Saint Peters University Hospital, Tufts University, and Women and Infants Hospital of Rhode Island. The authors also acknowledge C-TASC and The EMMES Corporations in providing data and imaging support. Genotyping was performed in the Department of Laboratory Medicine and Pathology, University of Minnesota. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).

Funding

This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) including American Recovery and Reinvestment Act funding via contract numbers HHSN275200800013C; HHSN275200800002I; HHSN27500006; HHSN275200800003IC; HHSN275200800014C; HHSN275200800012C; HHSN275200800028C; HHSN275201000009C and HHSN27500008. Additional support was obtained from the NIH Office of the Director, the National Institute on Minority Health and Health Disparities (NIMHD) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

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Authors and Affiliations

  1. Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Dr, 6710B-3204, Bethesda, MD, 20892-7004, USA

    Fasil Tekola-Ayele, Marion Ouidir, Deepika Shrestha, Tsegaselassie Workalemahu, Mohammad L. Rahman, Pauline Mendola, Katherine L. Grantz, Stefanie N. Hinkle & Cuilin Zhang

  2. Department of Population Medicine and Harvard Pilgrim Healthcare Institute, Harvard Medical School, Boston, MA, USA

    Mohammad L. Rahman

  3. Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA

    Pauline Mendola

  4. Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    Jing Wu

Authors
  1. Fasil Tekola-Ayele
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  2. Marion Ouidir
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  3. Deepika Shrestha
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  4. Tsegaselassie Workalemahu
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  7. Katherine L. Grantz
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  9. Jing Wu
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  10. Cuilin Zhang
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Contributions

FT-A conceived and designed this study; MO, FT-A, DS and JW performed statistical analyses. FT-A wrote the draft manuscript. All authors contributed to interpretation of the results, provided critical intellectual content, and approved the final manuscript.

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Correspondence to Fasil Tekola-Ayele.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

The study was approved by the institutional review boards of NICHD and each of the participating clinic sites.

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Written informed consent was obtained from all study participants.

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Tekola-Ayele, F., Ouidir, M., Shrestha, D. et al. Admixture mapping identifies African and Amerindigenous local ancestry loci associated with fetal growth. Hum Genet 140, 985–997 (2021). https://doi.org/10.1007/s00439-021-02265-4

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