Person: Whelan, Christopher W.
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Publication Ultra-rare disruptive and damaging mutations influence educational attainment in the general population
(2016) Ganna, Andrea; Genovese, Giulio; Howrigan, Daniel; Byrnes, Andrea; Kurki, Mitja; Zekavat, Seyedeh M.; Whelan, Christopher W.; Kals, Mart; Nivard, Michel G.; Bloemendal, Alex; Bloom, Jonathan M.; Goldstein, Jacqueline I.; Poterba, Timothy; Seed, Cotton; Handsaker, Robert; Natarajan, Pradeep; Mägi, Reedik; Gage, Diane; Robinson, Elise; Metspalu, Andres; Salomaa, Veikko; Suvisaari, Jaana; Purcell, Shaun M.; Sklar, Pamela; Kathiresan, Sekar; Daly, Mark; McCarroll, Steven; Sullivan, Patrick F.; Palotie, Aarno; Esko, Tõnu; Hultman, Christina; Neale, BenjaminDisruptive and damaging ultra-rare variants (URVs) in highly constrained (HC) genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE; −3.1 months; P-value=3.3×10−8). This effect was stronger among high brain-expressed genes and explained more YOE variance than pathogenic copy number variation, but less than common variants. Disruptive and damaging URVs in HC genes influence the determinants of YOE in the general population.
Publication A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica
(Nature Publishing Group UK, 2018) Estrada, Karol; Whelan, Christopher W.; Zhao, Fengmei; Bronson, Paola; Handsaker, Robert; Sun, Chao; Carulli, John P.; Harris, Tim; Ransohoff, Richard M.; McCarroll, Steven; Day-Williams, Aaron G.; Greenberg, Benjamin M.; MacArthur, DanielNeuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients ( > 70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). Here, we meta-analyze whole-genome sequences from 86 NMO cases and 460 controls with genome-wide SNP array from 129 NMO cases and 784 controls to test for association with SNPs and copy number variation (total N = 215 NMO cases, 1244 controls). We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. Mendelian Randomization analysis reveals a significant causal effect of known systemic lupus erythematosus (SLE), but not multiple sclerosis (MS), risk variants in NMO-IgG+. Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS.