Whole-exome sequencing in multiplex preeclampsia families identifies novel candidate susceptibility genes

Phillip E Melton, Matthew P Johnson, Dnyanada Gokhale-Agashe, Alexander J Rea, Amir Ariff, Gemma Cadby, Juan M Peralta, Tegan J Mcnab, Richard Jn Allcock, Lawrence J Abraham, John Blangero, Shaun P Brennecke, Eric K Moses

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: Preeclampsia is a common and serious heritable disorder of human pregnancy. Although there have been notable successes in identification of maternal susceptibility genes a large proportion of the heritability of preeclampsia remains unaccounted for. It is has been postulated that rare variation may account for some of this missing heritability. In this study, we performed whole-exome sequencing (WES) in multiplex families to identify rare exonic risk variants.

METHODS: We conducted WES in 244 individuals from 34 Australian/New Zealand multiplex preeclampsia families. Variants were tested for association with preeclampsia using a threshold model and logistic regression.

RESULTS: We found significant association for two moderately rare missense variants, rs145743393 (Padj = 0.0032, minor allele frequency = 0.016) in the chromosome 1 open reading frame 35 (C1orf35) gene, and rs34270076 (Padj = 0.0128, minor allele frequency = 0.024) in the pyroglutamylated RFamide peptide receptor (QRFPR) gene. To replicate these associations we performed imputation in our Australian genome wide association scan for preeclampsia and found no significant exonic variants in either C1orf35 or QRFPR. However, 11 variants demonstrating nominal significance (P < 0.05) in the genomic region between QRFPR and annexin A5 (ANXA5) were identified. We further leveraged publicaly available genome-wide available summary data from the UK Biobank to investigate association of these two variants with the underlying clinical phenotypes of preeclampsia and detected nominal association (P = 0.03) with protein levels in females.

CONCLUSION: The study represents the first to use WES in multiplex families for preeclampsia and identifies two novel genes (QRFPR and C1orf35) not previously associated with preeclampsia and find nominal association of rs34270076 with protein levels, a key clinical feature of preeclampsia. We find further support for ANXA5 previously associated with pregnancy complications, including preeclampsia.

Original languageEnglish
Pages (from-to)997-1011
Number of pages15
JournalJournal of Hypertension
DOIs
Publication statusE-pub ahead of print - 9 Jan 2019

Fingerprint

Exome
Pre-Eclampsia
Genes
Chromosomes, Human, Pair 1
Open Reading Frames
Gene Frequency
Annexins
Peptide Receptors
Pregnancy Complications
Annexin A5
Genome-Wide Association Study
New Zealand
Proteins
Logistic Models
Mothers
Genome

Cite this

Melton, Phillip E ; Johnson, Matthew P ; Gokhale-Agashe, Dnyanada ; Rea, Alexander J ; Ariff, Amir ; Cadby, Gemma ; Peralta, Juan M ; Mcnab, Tegan J ; Allcock, Richard Jn ; Abraham, Lawrence J ; Blangero, John ; Brennecke, Shaun P ; Moses, Eric K. / Whole-exome sequencing in multiplex preeclampsia families identifies novel candidate susceptibility genes. In: Journal of Hypertension. 2019 ; pp. 997-1011.
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abstract = "OBJECTIVE: Preeclampsia is a common and serious heritable disorder of human pregnancy. Although there have been notable successes in identification of maternal susceptibility genes a large proportion of the heritability of preeclampsia remains unaccounted for. It is has been postulated that rare variation may account for some of this missing heritability. In this study, we performed whole-exome sequencing (WES) in multiplex families to identify rare exonic risk variants.METHODS: We conducted WES in 244 individuals from 34 Australian/New Zealand multiplex preeclampsia families. Variants were tested for association with preeclampsia using a threshold model and logistic regression.RESULTS: We found significant association for two moderately rare missense variants, rs145743393 (Padj = 0.0032, minor allele frequency = 0.016) in the chromosome 1 open reading frame 35 (C1orf35) gene, and rs34270076 (Padj = 0.0128, minor allele frequency = 0.024) in the pyroglutamylated RFamide peptide receptor (QRFPR) gene. To replicate these associations we performed imputation in our Australian genome wide association scan for preeclampsia and found no significant exonic variants in either C1orf35 or QRFPR. However, 11 variants demonstrating nominal significance (P < 0.05) in the genomic region between QRFPR and annexin A5 (ANXA5) were identified. We further leveraged publicaly available genome-wide available summary data from the UK Biobank to investigate association of these two variants with the underlying clinical phenotypes of preeclampsia and detected nominal association (P = 0.03) with protein levels in females.CONCLUSION: The study represents the first to use WES in multiplex families for preeclampsia and identifies two novel genes (QRFPR and C1orf35) not previously associated with preeclampsia and find nominal association of rs34270076 with protein levels, a key clinical feature of preeclampsia. We find further support for ANXA5 previously associated with pregnancy complications, including preeclampsia.",
author = "Melton, {Phillip E} and Johnson, {Matthew P} and Dnyanada Gokhale-Agashe and Rea, {Alexander J} and Amir Ariff and Gemma Cadby and Peralta, {Juan M} and Mcnab, {Tegan J} and Allcock, {Richard Jn} and Abraham, {Lawrence J} and John Blangero and Brennecke, {Shaun P} and Moses, {Eric K}",
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Whole-exome sequencing in multiplex preeclampsia families identifies novel candidate susceptibility genes. / Melton, Phillip E; Johnson, Matthew P; Gokhale-Agashe, Dnyanada; Rea, Alexander J; Ariff, Amir; Cadby, Gemma; Peralta, Juan M; Mcnab, Tegan J; Allcock, Richard Jn; Abraham, Lawrence J; Blangero, John; Brennecke, Shaun P; Moses, Eric K.

In: Journal of Hypertension, 09.01.2019, p. 997-1011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Whole-exome sequencing in multiplex preeclampsia families identifies novel candidate susceptibility genes

AU - Melton, Phillip E

AU - Johnson, Matthew P

AU - Gokhale-Agashe, Dnyanada

AU - Rea, Alexander J

AU - Ariff, Amir

AU - Cadby, Gemma

AU - Peralta, Juan M

AU - Mcnab, Tegan J

AU - Allcock, Richard Jn

AU - Abraham, Lawrence J

AU - Blangero, John

AU - Brennecke, Shaun P

AU - Moses, Eric K

PY - 2019/1/9

Y1 - 2019/1/9

N2 - OBJECTIVE: Preeclampsia is a common and serious heritable disorder of human pregnancy. Although there have been notable successes in identification of maternal susceptibility genes a large proportion of the heritability of preeclampsia remains unaccounted for. It is has been postulated that rare variation may account for some of this missing heritability. In this study, we performed whole-exome sequencing (WES) in multiplex families to identify rare exonic risk variants.METHODS: We conducted WES in 244 individuals from 34 Australian/New Zealand multiplex preeclampsia families. Variants were tested for association with preeclampsia using a threshold model and logistic regression.RESULTS: We found significant association for two moderately rare missense variants, rs145743393 (Padj = 0.0032, minor allele frequency = 0.016) in the chromosome 1 open reading frame 35 (C1orf35) gene, and rs34270076 (Padj = 0.0128, minor allele frequency = 0.024) in the pyroglutamylated RFamide peptide receptor (QRFPR) gene. To replicate these associations we performed imputation in our Australian genome wide association scan for preeclampsia and found no significant exonic variants in either C1orf35 or QRFPR. However, 11 variants demonstrating nominal significance (P < 0.05) in the genomic region between QRFPR and annexin A5 (ANXA5) were identified. We further leveraged publicaly available genome-wide available summary data from the UK Biobank to investigate association of these two variants with the underlying clinical phenotypes of preeclampsia and detected nominal association (P = 0.03) with protein levels in females.CONCLUSION: The study represents the first to use WES in multiplex families for preeclampsia and identifies two novel genes (QRFPR and C1orf35) not previously associated with preeclampsia and find nominal association of rs34270076 with protein levels, a key clinical feature of preeclampsia. We find further support for ANXA5 previously associated with pregnancy complications, including preeclampsia.

AB - OBJECTIVE: Preeclampsia is a common and serious heritable disorder of human pregnancy. Although there have been notable successes in identification of maternal susceptibility genes a large proportion of the heritability of preeclampsia remains unaccounted for. It is has been postulated that rare variation may account for some of this missing heritability. In this study, we performed whole-exome sequencing (WES) in multiplex families to identify rare exonic risk variants.METHODS: We conducted WES in 244 individuals from 34 Australian/New Zealand multiplex preeclampsia families. Variants were tested for association with preeclampsia using a threshold model and logistic regression.RESULTS: We found significant association for two moderately rare missense variants, rs145743393 (Padj = 0.0032, minor allele frequency = 0.016) in the chromosome 1 open reading frame 35 (C1orf35) gene, and rs34270076 (Padj = 0.0128, minor allele frequency = 0.024) in the pyroglutamylated RFamide peptide receptor (QRFPR) gene. To replicate these associations we performed imputation in our Australian genome wide association scan for preeclampsia and found no significant exonic variants in either C1orf35 or QRFPR. However, 11 variants demonstrating nominal significance (P < 0.05) in the genomic region between QRFPR and annexin A5 (ANXA5) were identified. We further leveraged publicaly available genome-wide available summary data from the UK Biobank to investigate association of these two variants with the underlying clinical phenotypes of preeclampsia and detected nominal association (P = 0.03) with protein levels in females.CONCLUSION: The study represents the first to use WES in multiplex families for preeclampsia and identifies two novel genes (QRFPR and C1orf35) not previously associated with preeclampsia and find nominal association of rs34270076 with protein levels, a key clinical feature of preeclampsia. We find further support for ANXA5 previously associated with pregnancy complications, including preeclampsia.

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DO - 10.1097/HJH.0000000000002023

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