Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at PLEKHG1

Kathryn J Gray^{1

2

3}, Vesela P Kovacheva⁴, Hooman Mirzakhani⁵, Andrew C Bjonnes^{2

3}, Berta Almoguera⁶, Andrew T DeWan⁷, Elizabeth W Triche⁸, Audrey F Saftlas⁹, Josephine Hoh¹⁰, Dale L Bodian¹¹, Elisabeth Klein¹¹, Kathi C Huddleston¹¹, Sue Ann Ingles¹², Charles J Lockwood¹³, Hakon Hakonarson¹⁴, Thomas F McElrath¹⁵, Jeffrey C Murray¹⁶, Melissa L Wilson¹², Errol R Norwitz¹⁷, S Ananth Karumanchi^{18

19}, Brian T Bateman⁵, Brendan J Keating²⁰, Richa Saxena^{5

2

3}

Affiliations

¹ From the Division of Maternal-Fetal Medicine (K.J.G., T.F.M.) kgray6@bwh.harvard.edu.
² Center for Genomic Medicine (K.J.G., A.C.B., R.S.).
³ Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.J.G., A.C.B., R.S.).
⁴ Department of Anesthesiology (V.P.K.).
⁵ Brigham and Women's Hospital, Boston, MA; Department of Anesthesia, Critical Care and Pain Medicine (H.M., B.T.B., R.S.).
⁶ Center for Applied Genomics, Children's Hospital of Philadelphia, PA (B.A., H.H.).
⁷ Department of Chronic Disease Epidemiology (A.T.D.).
⁸ Yale School of Public Health, New Haven, CT; Center for Outcomes Research and Evaluation, Yale School of Medicine, New Haven, CT (E.W.T.).
⁹ Department of Epidemiology, College of Public Health, University of Iowa (A.F.S.).
¹⁰ Department of Environmental Health Sciences (J.H.).
¹¹ Inova Translational Medicine Institute, Inova Health System, Falls Church, VA (D.L.B., E.K., K.C.H.).
¹² Department of Preventative Medicine, University of Southern California, Keck School of Medicine, Los Angeles (S.A.I., M.L.W.).
¹³ University of South Florida, Morsani College of Medicine, Tampa (C.J.L.).
¹⁴ Divisions of Human Genetics and Pulmonary Medicine, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (H.H.).
¹⁵ From the Division of Maternal-Fetal Medicine (K.J.G., T.F.M.).
¹⁶ Department of Pediatrics, Carver College of Medicine, University of Iowa (J.C.M.).
¹⁷ Department of Obstetrics and Gynecology, Tufts Medical Center, Boston, MA (E.R.N.).
¹⁸ Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA (S.A.K.).
¹⁹ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (S.A.K.).
²⁰ Department of Surgery and Pediatrics, University of Pennsylvania, Philadelphia (B.J.K.).

PMID: 29967039
PMCID: PMC6043396
DOI: 10.1161/HYPERTENSIONAHA.117.10688

Multicenter Study

Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at PLEKHG1

Kathryn J Gray et al. Hypertension. 2018 Aug.

. 2018 Aug;72(2):408-416.

doi: 10.1161/HYPERTENSIONAHA.117.10688. Epub 2018 Jul 2.

Authors

Affiliations

¹ From the Division of Maternal-Fetal Medicine (K.J.G., T.F.M.) kgray6@bwh.harvard.edu.
² Center for Genomic Medicine (K.J.G., A.C.B., R.S.).
³ Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (K.J.G., A.C.B., R.S.).
⁴ Department of Anesthesiology (V.P.K.).
⁵ Brigham and Women's Hospital, Boston, MA; Department of Anesthesia, Critical Care and Pain Medicine (H.M., B.T.B., R.S.).
⁶ Center for Applied Genomics, Children's Hospital of Philadelphia, PA (B.A., H.H.).
⁷ Department of Chronic Disease Epidemiology (A.T.D.).
⁸ Yale School of Public Health, New Haven, CT; Center for Outcomes Research and Evaluation, Yale School of Medicine, New Haven, CT (E.W.T.).
⁹ Department of Epidemiology, College of Public Health, University of Iowa (A.F.S.).
¹⁰ Department of Environmental Health Sciences (J.H.).
¹¹ Inova Translational Medicine Institute, Inova Health System, Falls Church, VA (D.L.B., E.K., K.C.H.).
¹² Department of Preventative Medicine, University of Southern California, Keck School of Medicine, Los Angeles (S.A.I., M.L.W.).
¹³ University of South Florida, Morsani College of Medicine, Tampa (C.J.L.).
¹⁴ Divisions of Human Genetics and Pulmonary Medicine, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (H.H.).
¹⁵ From the Division of Maternal-Fetal Medicine (K.J.G., T.F.M.).
¹⁶ Department of Pediatrics, Carver College of Medicine, University of Iowa (J.C.M.).
¹⁷ Department of Obstetrics and Gynecology, Tufts Medical Center, Boston, MA (E.R.N.).
¹⁸ Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA (S.A.K.).
¹⁹ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (S.A.K.).
²⁰ Department of Surgery and Pediatrics, University of Pennsylvania, Philadelphia (B.J.K.).

PMID: 29967039
PMCID: PMC6043396
DOI: 10.1161/HYPERTENSIONAHA.117.10688

Abstract

The genetic susceptibility to preeclampsia, a pregnancy-specific complication with significant maternal and fetal morbidity, has been poorly characterized. To identify maternal genes associated with preeclampsia risk, we assembled 498 cases and 1864 controls of European ancestry from preeclampsia case-control collections in 5 different US sites (with additional matched population controls), genotyped samples on a cardiovascular gene-centric array composed of variants from ≈2000 genes selected based on prior genetic studies of cardiovascular and metabolic diseases and performed case-control genetic association analysis on 27 429 variants passing quality control. In silico replication testing of 9 lead signals with P<10^-⁴ was performed in independent European samples from the SOPHIA (Study of Pregnancy Hypertension in Iowa) and Inova cohorts (212 cases, 456 controls). Multiethnic assessment of lead signals was then performed in samples of black (26 cases, 136 controls), Hispanic (132 cases, 468 controls), and East Asian (9 cases, 80 controls) ancestry. Multiethnic meta-analysis (877 cases, 3004 controls) revealed a study-wide statistically significant association of the rs9478812 variant in the pleiotropic PLEKHG1 gene (odds ratio, 1.40 [1.23-1.60]; P_meta=5.90×10^-7). The rs9478812 effect was even stronger in the subset of European cases with known early-onset preeclampsia (236 cases diagnosed <37 weeks, 1864 controls; odds ratio, 1.59 [1.27-1.98]; P=4.01×10^-5). PLEKHG1 variants have previously been implicated in genome-wide association studies of blood pressure, body weight, and neurological disorders. Although larger studies are required to further define maternal preeclampsia heritability, this study identifies a novel maternal risk locus for further investigation.

Keywords: genetic association studies; hypertension; population control; preeclampsia; pregnancy.

PubMed Disclaimer

Conflict of interest statement

Conflict(s) of Interest/Disclosure(s). All other authors have no conflicts.

Figures

**Figure 1**
Manhattan and q-q plots of PE association results in women of European ancestry (SNPs >1% frequency *for n* =498 cases, n =1,864 controls).

See this image and copyright information in PMC

Comment in

Genes for Preeclampsia: An Opportunity for Blood Pressure Genomics.
Ehret G. Ehret G. Hypertension. 2018 Aug;72(2):285-286. doi: 10.1161/HYPERTENSIONAHA.118.10840. Epub 2018 Jul 2. Hypertension. 2018. PMID: 29967038 Free PMC article. No abstract available.

References

1. Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ. Pre-eclampsia. Lancet. 2016;387(10022):999–1011. - PubMed
1. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet. 2001;357(9273):2002–2006. - PubMed
1. Wikström A-K, Haglund B, Olovsson M, Lindeberg SN. The risk of maternal ischaemic heart disease after gestational hypertensive disease. BJOG. 2005;112(11):1486–1491. - PubMed
1. Pell JP, Smith GCS, Walsh D. Pregnancy complications and subsequent maternal cerebrovascular events: a retrospective cohort study of 119,668 births. Am J Epidemiol. 2004;159(4):336–342. - PubMed
1. Kestenbaum B, Seliger SL, Easterling TR, Gillen DL, Critchlow CW, Stehman-Breen CO, Schwartz SM. Cardiovascular and thromboembolic events following hypertensive pregnancy. Am J Kidney Dis. 2003;42(5):982–989. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at PLEKHG1

Affiliations

Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at PLEKHG1

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases