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<p>Most pregnancies are affected by nausea and vomiting, but the most severe form—hyperemesis gravidarum—can be life threatening. Here we performed a multi-ancestry genome-wide association study of hyperemesis gravidarum in 10,974 cases and 461,461 controls across European, Asian, African and Latino ancestries. We identified ten associations: four identified previously (<i>GDF15</i>, <i>IGFBP7</i>, <i>PGR</i> and <i>GFRAL</i>) and six additional loci (<i>SLITRK1</i>, <i>SYN3</i>, <i>IGSF11</i>, <i>FSHB</i>, <i>TCF7L2</i> and <i>CDH9</i>). Downstream analyses revealed <i>GDF15</i> and <i>TCF7L2</i> expression primarily in extravillous trophoblasts, with opposing effects for <i>GDF15</i> between maternal and fetal genotype. Conversely, <i>IGFBP7</i> and <i>PGR</i> were expressed primarily in maternal spiral arteries, with effects limited to the maternal genome. Selected loci were associated with abnormal pregnancy weight gain, duration, birth weight and pre-eclampsia. Functional studies identified additional associations including antisense <i>IGFBP7-AS1</i> and protein ACP1. Potential roles for candidate genes in appetite, insulin signaling and brain plasticity provide pathways to explore etiological mechanisms and therapeutic avenues.</p>

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Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting

  • 期刊论文

  • 发表日期：

    2026年4月14日

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  • Marlena Fejzo,
  • Xinran Wang,
  • Qing Tan,
  • Julia Zöllner,
  • Natàlia Pujol-Gualdo,
  • Triin Laisk,
  • Andres Metspalu,
  • Lili Milani,
  • Tõnu Esko,
  • Reedik Mägi,
  • Mari Nelis,
  • Georgi Hudjashov,
  • Sarah Finer,
  • David A. van Heel,
  • Eamonn Maher,
  • Shabana Chaudhary,
  • Joseph Gafton,
  • Karen A. Hunt,
  • Shapna Hussain,
  • Kamrul Islam,
  • Mohammed Bodrul Mazid,
  • Elizabeth Owor,
  • Jessry Russell,
  • Nishat Safa,
  • John Solly,
  • Marie Spreckley,
  • Jan Whalley,
  • Ishevanhu Zengeya,
  • Emily Mantle,
  • Shaheen Akhtar,
  • Samina Ashraf,
  • Dan Mason,
  • John Wright,
  • Daniel MacArthur,
  • Michael Simpson,
  • Richard C. Trembath,
  • Gerome Breen,
  • Raymond Chung,
  • Sang Hyuck Lee,
  • Omar Asgar,
  • Joanne Harvey,
  • Karen Tricker,
  • Caroline Winckley,
  • Hanifa Khatun,
  • Amna Asif,
  • Claudia Langenberg,
  • Grainne Colligan,
  • Ceri Durham,
  • Bill Newman,
  • Ahsan Khan,
  • Hilary Martin,
  • Teng Heng,
  • Matt Hurles,
  • Vivek Iyer,
  • Georgios Kalantzis,
  • Vladimir Ovchinnikov,
  • Iaroslav Popov,
  • Klaudia Walter,
  • Panos Deloukas,
  • David Collier,
  • Ana Angel,
  • Saeed Bidi,
  • Fabiola Eto,
  • Chris Griffiths,
  • Sam Hodgson,
  • Benjamin M. Jacobs,
  • Rohini Mathur,
  • Caroline Morton,
  • Asma Qureshi,
  • Stuart Rison,
  • Annum Salman,
  • Miriam Samuel,
  • Moneeza K. Siddiqui,
  • Daniel Stow,
  • Sabina Yasmin,
  • Sheik Dowlut,
  • Ben Brumpton,
  • Laxmi Bhatta,
  • Kristian Hveem,
  • Elizabeth A. Jasper,
  • Digna R. Velez Edwards,
  • Jacklyn N. Hellwege,
  • Todd Edwards,
  • Gail P. Jarvik,
  • Yuan Luo,
  • Atlas Khan,
  • Kimber MacGibbon,
  • Yuan Gao,
  • Gaoxiang Ge,
  • Inna Averbukh,
  • Erin Soon,
  • Michael Angelo,
  • Per Magnus,
  • Stefan Johansson,
  • Pål R. Njølstad,
  • Artem Kim,
  • Steven Gazal,
  • Marc Vaudel,
  • Chang April Shu,
  • Nicholas Mancuso

摘要

Most pregnancies are affected by nausea and vomiting, but the most severe form—hyperemesis gravidarum—can be life threatening. Here we performed a multi-ancestry genome-wide association study of hyperemesis gravidarum in 10,974 cases and 461,461 controls across European, Asian, African and Latino ancestries. We identified ten associations: four identified previously (GDF15, IGFBP7, PGR and GFRAL) and six additional loci (SLITRK1, SYN3, IGSF11, FSHB, TCF7L2 and CDH9). Downstream analyses revealed GDF15 and TCF7L2 expression primarily in extravillous trophoblasts, with opposing effects for GDF15 between maternal and fetal genotype. Conversely, IGFBP7 and PGR were expressed primarily in maternal spiral arteries, with effects limited to the maternal genome. Selected loci were associated with abnormal pregnancy weight gain, duration, birth weight and pre-eclampsia. Functional studies identified additional associations including antisense IGFBP7-AS1 and protein ACP1. Potential roles for candidate genes in appetite, insulin signaling and brain plasticity provide pathways to explore etiological mechanisms and therapeutic avenues.