Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology.
There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-08-01
|
| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1007501&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1839634503021101056 |
|---|---|
| author | Laurence J Howe Myoung Keun Lee Gemma C Sharp George Davey Smith Beate St Pourcain John R Shaffer Kerstin U Ludwig Elisabeth Mangold Mary L Marazita Eleanor Feingold Alexei Zhurov Evie Stergiakouli Jonathan Sandy Stephen Richmond Seth M Weinberg Gibran Hemani Sarah J Lewis |
| author_facet | Laurence J Howe Myoung Keun Lee Gemma C Sharp George Davey Smith Beate St Pourcain John R Shaffer Kerstin U Ludwig Elisabeth Mangold Mary L Marazita Eleanor Feingold Alexei Zhurov Evie Stergiakouli Jonathan Sandy Stephen Richmond Seth M Weinberg Gibran Hemani Sarah J Lewis |
| author_sort | Laurence J Howe |
| collection | DOAJ |
| description | There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum. |
| format | Article |
| id | doaj-art-fce4f3a95f2a43b4beeacd55bb4e7ff5 |
| institution | Matheson Library |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2018-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-fce4f3a95f2a43b4beeacd55bb4e7ff52025-07-10T05:30:56ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042018-08-01148e100750110.1371/journal.pgen.1007501Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology.Laurence J HoweMyoung Keun LeeGemma C SharpGeorge Davey SmithBeate St PourcainJohn R ShafferKerstin U LudwigElisabeth MangoldMary L MarazitaEleanor FeingoldAlexei ZhurovEvie StergiakouliJonathan SandyStephen RichmondSeth M WeinbergGibran HemaniSarah J LewisThere is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1007501&type=printable |
| spellingShingle | Laurence J Howe Myoung Keun Lee Gemma C Sharp George Davey Smith Beate St Pourcain John R Shaffer Kerstin U Ludwig Elisabeth Mangold Mary L Marazita Eleanor Feingold Alexei Zhurov Evie Stergiakouli Jonathan Sandy Stephen Richmond Seth M Weinberg Gibran Hemani Sarah J Lewis Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology. PLoS Genetics |
| title | Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology. |
| title_full | Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology. |
| title_fullStr | Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology. |
| title_full_unstemmed | Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology. |
| title_short | Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology. |
| title_sort | investigating the shared genetics of non syndromic cleft lip palate and facial morphology |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1007501&type=printable |
| work_keys_str_mv | AT laurencejhowe investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT myoungkeunlee investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT gemmacsharp investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT georgedaveysmith investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT beatestpourcain investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT johnrshaffer investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT kerstinuludwig investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT elisabethmangold investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT marylmarazita investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT eleanorfeingold investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT alexeizhurov investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT eviestergiakouli investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT jonathansandy investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT stephenrichmond investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT sethmweinberg investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT gibranhemani investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology AT sarahjlewis investigatingthesharedgeneticsofnonsyndromiccleftlippalateandfacialmorphology |