TY - JOUR
T1 - Transmission disequilibrium of small CNVs in simplex autism
AU - Krumm, Niklas
AU - O'Roak, Brian J.
AU - Karakoc, Emre
AU - Mohajeri, Kiana
AU - Nelson, Ben
AU - Vives, Laura
AU - Jacquemont, Sebastien
AU - Munson, Jeff
AU - Bernier, Raphe
AU - Eichler, Evan E.
N1 - Funding Information:
We thank the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute Grand Opportunity (GO) Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women’s Health Initiative Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). We thank all the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R.B., J. Constantino, E. Cook, E. Fombonne, D. Geschwind, E. Hanson, D. Grice, A. Klin, R. Kochel, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We also acknowledge M. State and the SSC Genetics Consortium for providing Illumina genotyping data and T. Lehner and the Autism Sequencing Consortium for data exchange among the participating groups. We are grateful for helpful discussion and manuscript preparation from T. Brown, P. Sudmant, and all members of the Eichler lab. This work was supported by the Simons Foundation Autism Research Initiative (SFARI 137578 and 191889 to E.E.E., J.S., and R.B.) and NIH HD065285 (E.E.E. and J.S.). E.B. is an Alfred P. Sloan Research Fellow. E.E.E. is an Investigator of the Howard Hughes Medical Institute and is on the scientific advisory boards for Pacific Biosciences, Inc., SynapDx Corp., and DNAnexus, Inc.
PY - 2013/10/3
Y1 - 2013/10/3
N2 - We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.
AB - We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.
UR - http://www.scopus.com/inward/record.url?scp=84885301258&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885301258&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2013.07.024
DO - 10.1016/j.ajhg.2013.07.024
M3 - Article
C2 - 24035194
AN - SCOPUS:84885301258
SN - 0002-9297
VL - 93
SP - 595
EP - 606
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -