Genetic analysis of hyperemesis gravidarum reveals association with intracellular calcium release channel (RYR2).
Hyperemesis Gravidarum (HG), severe nausea/vomiting in pregnancy (NVP), can cause poor maternal/fetal outcomes. Genetic predisposition suggests the genetic component is essential in discovering an etiology. We performed whole-exome sequencing of 5 families followed by analysis of variants in 584 cases/431 controls. Variants in RYR2 segregated with disease in 2 families. The novel variant L3277R was not found in any case/control. The rare variant, G1886S was more common in cases (p = 0.046) and extreme cases (p = 0.023). Replication of G1886S using Norwegian/Australian data was supportive. Common variants rs790899 and rs1891246 were significantly associated with HG and weight loss. Copy-number analysis revealed a deletion in a patient. RYR2 encodes an intracellular calcium release channel involved in vomiting, cyclic-vomiting syndrome, and is a thyroid hormone target gene. Additionally, RYR2 is a downstream drug target of Inderal, used to treat HG and CVS. Thus, herein we provide genetic evidence for a pathway and therapy for HG.
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Department of Maternal-Fetal Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: mfejzo@mednet.ucla.edu.
Marlena Schoenberg
MS
Fejzo
Norwegian Institute of Public Health, Oslo Norway.
Ronny
R
Myhre
Psychiatric Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Lucía
L
Colodro-Conde
Hyperemesis Education and Research Foundation, Damascus, OR, USA.
Kimber W
KW
MacGibbon
Departments of Biostatistics, Biomathematics, & Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Janet S
JS
Sinsheimer
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
M V Prasad Linga
MVPL
Reddy
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Päivi
P
Pajukanta
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
Dale R
DR
Nyholt
Queensland Brain Institute and Centre for Advanced Imaging, University of Queensland, Brisbane, Australia.
Margaret J
MJ
Wright
Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Nicholas G
NG
Martin
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Stephanie M
SM
Engel
Psychiatric Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Sarah E
SE
Medland
Norwegian Institute of Public Health, Oslo Norway.
Per
P
Magnus
Department of Maternal-Fetal Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Patrick M
PM
Mullin
D001315:Australia; D002118:Calcium / Q000378:metabolism*; D015331:Cohort Studies; D059472:Exome / Q000235:genetics; D005190:Family; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006939:Hyperemesis Gravidarum / Q000235:genetics*; D042541:Intracellular Space / Q000378:metabolism*; D008297:Male; D009664:Norway; D010288:Parenteral Nutrition; D010375:Pedigree; D011247:Pregnancy; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014481:United States
D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium
Hyperemesis gravidarum; Nausea; Pregnancy; RYR2; Vomiting
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