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Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth
Journal article   Open access   Peer reviewed

Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth

Johanna M Huusko, Minna K Karjalainen, Britney E Graham, Ge Zhang, Emily G Farrow, Neil A Miller, Bo Jacobsson, Haley R Eidem, Jeffrey C Murray, Bruce Bedell, …
PLoS genetics, Vol.14(7), pp.e1007394-e1007394
2018
DOI: 10.1371/journal.pgen.1007394
PMCID: PMC6042692
PMID: 30001343
url
https://doi.org/10.1371/journal.pgen.1007394View
Published (Version of record) Open Access

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Abstract

Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2–4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like ( HSPA1L ), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs . 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB. Preterm birth is the leading cause of infant mortality, and prematurity is further associated with serious morbidities in later life. Genetic and environmental risk factors play a role in the susceptibility to preterm birth. Despite numerous studies, the genetic basis for preterm birth remains poorly defined. We investigated the presence of rare, possibly risk associated nucleotide variants in mothers with spontaneous preterm births (SPTB). The first set of mothers with family history of recurrent preterm births was of northern Finnish origin. An additional set of mothers (sister pairs, both giving birth preterm) of European origin was also studied. Whole exome sequencing identified multiple rare, likely damaging HSPA1L variants in several families affected by SPTB, and this gene was associated with the glucocorticoid receptor signaling pathway. Potential involvement of one of the HSPA1L variants in SPTB was further supported by large GWAS dataset. In addition, this variant alters protein post-translational modification potential, and thus may affect protein stability and its function as a chaperone.
 Medicine and Health Sciences Engineering and Technology Biology and Life Sciences Computer and Information Sciences

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