title: Exome sequencing in pooled DNA samples to identify maternal pre-eclampsia risk variants.
abstract: Pre-eclampsia is a common pregnancy disorder that is a major cause for maternal and perinatal mortality and morbidity. Variants predisposing to pre-eclampsia might be under negative evolutionary selection that is likely to keep their population frequencies low. We exome sequenced samples from a hundred Finnish pre-eclamptic women in pools of ten to screen for low-frequency, large-effect risk variants for pre-eclampsia. After filtering and additional genotyping steps, we selected 28 low-frequency missense, nonsense and splice site variants that were enriched in the pre-eclampsia pools compared to reference data, and genotyped the variants in 1353 pre-eclamptic and 699 non-pre-eclamptic women to test the association of them with pre-eclampsia and quantitative traits relevant for the disease. Genotypes from the SISu project (n = 6118 exome sequenced Finnish samples) were included in the binary trait association analysis as a population reference to increase statistical power. In these analyses, none of the variants tested reached genome-wide significance. In conclusion, the genetic risk for pre-eclampsia is likely complex even in a population isolate like Finland, and larger sample sizes will be necessary to detect risk variants.
authors.affiliation: Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Tea
authors.initials: T
authors.lastname: Kaartokallio
authors.affiliation: Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, SE-141 83 Stockholm, Sweden.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Wang
authors.affiliation: Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Heinonen
authors.affiliation: Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.|Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.|PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Kajantie
authors.affiliation: Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Katja
authors.initials: K
authors.lastname: Kivinen
authors.affiliation: PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.|Department of Government services, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.affiliation: Department of Orthopedics, Karolinska University Hospital, Stockholm, Sweden.|Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institutet, SE-141 86 Stockholm, Sweden.
authors.forename: Paul
authors.initials: P
authors.lastname: Gerdhem
authors.affiliation: Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, SE-141 83 Stockholm, Sweden.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiao
authors.affiliation: Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, SE-141 83 Stockholm, Sweden.|Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland.|Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Laivuori
mesh_terms: D000328:Adult; D059472:Exome / Q000235:genetics*; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D054238:Perinatal Mortality; D011225:Pre-Eclampsia / Q000235:genetics* / Q000473:pathology; D011247:Pregnancy; D012307:Risk Factors; D000073359:Exome Sequencing