A Novel Test for Recessive Contributions to Complex Diseases Implicates Bardet-Biedl Syndrome Gene BBS10 in Idiopathic Type 2 Diabetes and Obesity Elaine T.

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A Novel Test for Recessive Contributions to Complex Diseases Implicates Bardet-Biedl Syndrome Gene BBS10 in Idiopathic Type 2 Diabetes and Obesity Elaine T. Lim, Yangfan P. Liu, Yingleong Chan, Tuomi Tiinamaija, AnnMari Käräjämäki, Erik Madsen, David M. Altshuler, Soumya Raychaudhuri, Leif Groop, Jason Flannick, Joel N. Hirschhorn, Nicholas Katsanis, Mark J. Daly The American Journal of Human Genetics Volume 95, Issue 5, Pages 509-520 (November 2014) DOI: 10.1016/j.ajhg.2014.09.015 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Scenarios to Illustrate p Values Obtained with Fisher’s Exact Test on the Homozygous Counts (A) p values obtained if there are 1, 2, 4, 8, 20, or 40 genes with complete penetrance that are causal for the disease. (B) p values with different percentages of variance explained by the homozygotes (aa) in the cases, assuming complete penetrance. This is an ideal scenario and the power for detection will be lower if the variants exhibit incomplete penetrance or if there are fewer controls available. The American Journal of Human Genetics 2014 95, 509-520DOI: (10.1016/j.ajhg.2014.09.015) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Power Calculations for Various Tests in Detecting Recessive Variants with OR = 10 and Disease Prevalence of 1% in 5,000 Case Subjects and 5,000 Control Subjects (A) Power calculations for detecting recessive variants across different allele frequencies by using two allelic tests (chi-square and TDT), as well as two recessive tests (Fisher’s exact test on the homozygotes [Hom-FET] and RAFT). (B) Graphical representation for the power calculations for chi-square, TDT, Hom-FET, and RAFT across various allele-frequency ranges from 0.1% to 20% with the same parameters. (C) Power calculations for the same scenario but a variant with 2% allele frequency across various recessive ORs from 1.2 to 2,000. The American Journal of Human Genetics 2014 95, 509-520DOI: (10.1016/j.ajhg.2014.09.015) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 The p.Ile397Val Residue Is Not Conserved across 46 Vertebrates, and the Valine Residue Is Found in Other Vertebrates The American Journal of Human Genetics 2014 95, 509-520DOI: (10.1016/j.ajhg.2014.09.015) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 4 In Vivo Knockdown and Rescue Experiments in Zebrafish for BBS10 c.1189A>G (A) Lateral view (top) and dorsal view (bottom) of representative zebrafish embryos at the 10-somite stage. In comparison with control embryos, embryos injected with bbs10 translation blocker (TB) morpholino exhibited an expanded body gap angle (marked with blue lines in lateral view) and elongated somites (marked with blue lines in dorsal view) and kinked notochord (marked with blue arrows in dorsal view), indicating convergent extension (CE) defects. Scale bar represents 100 μM. (B) Distribution of zebrafish embryos with different CE defect severity levels based on previously established criteria (class I, mild; class II, severe15–17 in each condition). Coinjection of human wild-type human BBS10 mRNA (bbs10 TB + BBS10 wild-type) rescues CE defect in bbs10 TB-injected embryos, while coinjection of human BBS10 mRNA with c.1189A>G mutation (bbs10 TB + BBS10 c.1189A>G) does not. Chi-square test was used to test significance; ∗∗∗p < 0.001. (C) The relative mRNA levels of the genes pdk2 and runx1 in 4 days postfertilization (dpf) zebrafish embryos treated with 1% D-glucose at 1 dpf. Decreased mRNA levels in bbs10 TB-injected embryos were significantly rescued by coinjection of human wild-type human BBS10 mRNA (bbs10 TB + BBS10 wild-type), but not coinjection of human BBS10 mRNA encoding the c.1189A>G mutation (bbs10 TB + BBS10 c.1189A>G). t test was used to test significance; ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. The American Journal of Human Genetics 2014 95, 509-520DOI: (10.1016/j.ajhg.2014.09.015) Copyright © 2014 The American Society of Human Genetics Terms and Conditions