多效性方法揭示了多种族三人组的 GWAS 多个新位点口面部裂隙之间的遗传重叠.

Based on epidemiologic and embryologic patterns, nonsyndromic orofacial
clefts- the most common craniofacial birth defects in humans- are commonly
categorized into cleft lip with or without cleft palate (CL/P) and cleft
palate alone (CP), which are traditionally considered to be etiologically
distinct. 然而, some evidence of shared genetic risk in IRF6, GRHL3 and
ARHGAP29 regions exists; only FOXE1 has been recognized as significantly
associated with both CL/P and CP in genome-wide association studies (GWAS).
We used a new statistical approach, PLACO (pleiotropic analysis under
composite null), on a combined multi-ethnic GWAS of 2,771 CL/P and 611 CP
case-parent trios. At the genome-wide significance threshold of 5 × 10-8,
PLACO identified 1 locus in 1q32.2 (IRF6) that appears to increase risk for
one OFC subgroup but decrease risk for the other. At a suggestive
significance threshold of 10-6, we found 5 more loci with compelling
candidate genes having opposite effects on CL/P and CP: 1p36.13 (PAX7),
3q29 (DLG1), 4p13 (LIMCH1), 4q21.1 (SHROOM3) and 17q22 (NOG). 此外,
we replicated the recognized shared locus 9q22.33 (FOXE1), and identified 2
loci in 19p13.12 (RAB8A) and 20q12 (MAFB) that appear to influence risk of
both CL/P and CP in the same direction. We found locus-specific effects may
vary by racial/ethnic group at these regions of genetic overlap, and failed
to find evidence of sex-specific differences. We confirmed shared etiology
of the two OFC subtypes comprising CL/P, and additionally found suggestive
evidence of differences in their pathogenesis at 2 loci of genetic overlap.
Our novel findings include 6 new loci of genetic overlap between CL/P and
CP; 3 new loci between pairwise OFC subtypes; 和 4 loci not previously
implicated in OFCs. Our in-silico validation showed PLACO is robust to
subtype-specific effects, and can achieve massive power gains over existing
approaches for identifying genetic overlap between disease subtypes. 在
summary, we found suggestive evidence for new genetic regions and confirmed
some recognized OFC genes either exerting shared risk or with opposite
effects on risk to OFC subtypes.