Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts

John R. Shaffer*, Jessica LeClair, Jenna C. Carlson, Eleanor Feingold, Carmen J. Buxó, Kaare Christensen, Frederic W.B. Deleyiannis, L. Leigh Field, Jacqueline T. Hecht, Lina Moreno, Ieda M. Orioli, Carmencita Padilla, Alexandre R. Vieira, George L. Wehby, Jeffrey C. Murray, Seth M. Weinberg, Mary L. Marazita, Elizabeth J. Leslie

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the “missing” heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP-Seq studies in craniofacial tissues or cell lines contained multiple low-frequency (0.01–1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low-frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p-value =.0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p-value =.001). These findings suggest that low-frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.

Original languageEnglish
JournalAmerican Journal of Medical Genetics, Part A
Volume179
Issue number3
Pages (from-to)467-474
ISSN1552-4825
DOIs
Publication statusPublished - 1. Mar 2019

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Nucleic Acid Regulatory Sequences
Cleft Palate
Cleft Lip
Alleles
Cell Line

Keywords

  • cleft lip
  • cleft palate
  • genetic association
  • orofacial cleft

Cite this

Shaffer, John R. ; LeClair, Jessica ; Carlson, Jenna C. ; Feingold, Eleanor ; Buxó, Carmen J. ; Christensen, Kaare ; Deleyiannis, Frederic W.B. ; Field, L. Leigh ; Hecht, Jacqueline T. ; Moreno, Lina ; Orioli, Ieda M. ; Padilla, Carmencita ; Vieira, Alexandre R. ; Wehby, George L. ; Murray, Jeffrey C. ; Weinberg, Seth M. ; Marazita, Mary L. ; Leslie, Elizabeth J. / Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts. In: American Journal of Medical Genetics, Part A. 2019 ; Vol. 179, No. 3. pp. 467-474.
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title = "Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts",
abstract = "Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the “missing” heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP-Seq studies in craniofacial tissues or cell lines contained multiple low-frequency (0.01–1{\%}) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low-frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p-value =.0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p-value =.001). These findings suggest that low-frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.",
keywords = "cleft lip, cleft palate, genetic association, orofacial cleft",
author = "Shaffer, {John R.} and Jessica LeClair and Carlson, {Jenna C.} and Eleanor Feingold and Bux{\'o}, {Carmen J.} and Kaare Christensen and Deleyiannis, {Frederic W.B.} and Field, {L. Leigh} and Hecht, {Jacqueline T.} and Lina Moreno and Orioli, {Ieda M.} and Carmencita Padilla and Vieira, {Alexandre R.} and Wehby, {George L.} and Murray, {Jeffrey C.} and Weinberg, {Seth M.} and Marazita, {Mary L.} and Leslie, {Elizabeth J.}",
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Shaffer, JR, LeClair, J, Carlson, JC, Feingold, E, Buxó, CJ, Christensen, K, Deleyiannis, FWB, Field, LL, Hecht, JT, Moreno, L, Orioli, IM, Padilla, C, Vieira, AR, Wehby, GL, Murray, JC, Weinberg, SM, Marazita, ML & Leslie, EJ 2019, 'Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts', American Journal of Medical Genetics, Part A, vol. 179, no. 3, pp. 467-474. https://doi.org/10.1002/ajmg.a.61002

Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts. / Shaffer, John R.; LeClair, Jessica; Carlson, Jenna C.; Feingold, Eleanor; Buxó, Carmen J.; Christensen, Kaare; Deleyiannis, Frederic W.B.; Field, L. Leigh; Hecht, Jacqueline T.; Moreno, Lina; Orioli, Ieda M.; Padilla, Carmencita; Vieira, Alexandre R.; Wehby, George L.; Murray, Jeffrey C.; Weinberg, Seth M.; Marazita, Mary L.; Leslie, Elizabeth J.

In: American Journal of Medical Genetics, Part A, Vol. 179, No. 3, 01.03.2019, p. 467-474.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts

AU - Shaffer, John R.

AU - LeClair, Jessica

AU - Carlson, Jenna C.

AU - Feingold, Eleanor

AU - Buxó, Carmen J.

AU - Christensen, Kaare

AU - Deleyiannis, Frederic W.B.

AU - Field, L. Leigh

AU - Hecht, Jacqueline T.

AU - Moreno, Lina

AU - Orioli, Ieda M.

AU - Padilla, Carmencita

AU - Vieira, Alexandre R.

AU - Wehby, George L.

AU - Murray, Jeffrey C.

AU - Weinberg, Seth M.

AU - Marazita, Mary L.

AU - Leslie, Elizabeth J.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the “missing” heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP-Seq studies in craniofacial tissues or cell lines contained multiple low-frequency (0.01–1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low-frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p-value =.0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p-value =.001). These findings suggest that low-frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.

AB - Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the “missing” heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP-Seq studies in craniofacial tissues or cell lines contained multiple low-frequency (0.01–1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low-frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p-value =.0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p-value =.001). These findings suggest that low-frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.

KW - cleft lip

KW - cleft palate

KW - genetic association

KW - orofacial cleft

U2 - 10.1002/ajmg.a.61002

DO - 10.1002/ajmg.a.61002

M3 - Journal article

VL - 179

SP - 467

EP - 474

JO - American Journal of Medical Genetics. Part A

JF - American Journal of Medical Genetics. Part A

SN - 1552-4825

IS - 3

ER -