Table 4.
Sequence Kernel Association Test (SKAT) of Binned Rare CASR Loss-of-Function Variants
| Code | Code Description | # Cases | p Value | Q-Value |
|---|---|---|---|---|
| 453.9 | embolism and thrombosis of unspecified site | 705 | 1.51E−14 | 9.26E−12 |
| 428.32 | diastolic heart failure, chronic | 467 | 4.1E−12 | 1.12E−9 |
| 788.33 | mixed incontinence (male, female) | 260 | 1.03E−10 | 1.59E−8 |
| 296.2 | major depressive disorder, single episode, unspecified degree | 248 | 3.56E−10 | 4.38E−8 |
| 790.4 | nonspecific elevations of transaminase or lactic dehydrogenase | 277 | 2.54E−9 | 2.6E−7 |
| 716.96 | arthropathy unspecified, lower leg | 306 | 2.26E−7 | 1.76E−5 |
| 427.1 | paroxysmal ventricular tachycardia | 471 | 8.81E−7 | 4.88E−5 |
| 820.8 | fracture of unspecified part of neck of femur, closed | 205 | 1.56E−6 | 6.71E−5 |
| 366.16 | senile nuclear sclerosis | 4,938 | 1.59E−6 | 6.76E−5 |
| 294.2 | dementia, without behavioral disturbance | 201 | 1.7E−6 | 6.98E−5 |
| 274 | gouty arthropathy | 349 | 1.71E−6 | 6.99E−5 |
| 715.15 | osteoarthritis, localized, primary, pelvic region and thigh | 293 | 2.48E−6 | 9.53E−5 |
| 998.59 | other postoperative infection | 423 | 4.42E−6 | .00016 |
| 211.3 | benign neoplasm of colon | 3,176 | 8.88E−6 | .00029 |
| 305 | alcohol abuse, unspecified drinking behavior | 223 | 9.24E−6 | .0003 |
| 224.6 | benign neoplasm of choroid | 233 | 1.67E−5 | .00051 |
| 573.8 | other specified disorders of liver | 205 | 2.59E−5 | .00074 |
| 785.6 | enlargement of lymph nodes | 609 | 3.01E−5 | .00083 |
| 493.91 | asthma, unspecified type, with status asthmaticus | 217 | 3.69E−5 | .00097 |
| 428.22 | systolic heart failure, chronic | 472 | 5.37E−5 | .0013 |
| 521.02 | dental caries extending into dentine | 248 | 6.13E−5 | .0014 |
| 794.31 | nonspecific abnormal electrocardiogram | 339 | 7.13E−5 | .0015 |
| 715.11 | osteoarthrosis, localized, primary, involving shoulder region | 229 | 7.48E−5 | .0016 |
Rare nonsense/frameshift and validated missense loss-of-function variants were combined and association with all clinical phenotypes determined by SKAT. Dataset for analysis included 25 males (61 ± 16.2 years, 96% northern European descent) and 30 females (55.5 ± 19 years, 100% northern European descent) with variants compared against 30,448 individuals without rare CASR variants. Three calls of an ICD9 were required to define a case, and covariates were sex, age, age2, and first four PCs (see Subjects and Methods). We chose an exploratory cutoff of p < 0.05, significant results were at p < 7.74E−5, when corrected for multiple testing (646 ICD9 codes with ≥200 cases irrespective of genotype). Variants used for analysis were p.Ala19Pro (c.55G>C), p.Leu37Alafs∗11 (c.108dup), p.Arg66His (c.197G>A), p.Met74Leu (c.220A>C), p.Cys101∗ (c.303C>A), p.Arg227∗ (c.679C>T), p.Trp293∗ (c.879G>A), p.Cys395Arg (c.1183T>C), p.Glu399Asp (c.1197G>C), p.Ser417Cys (c.1250C>G), p.Ala430Thr (c.1288G>A), p.Cys437Arg (c.1309T>C), p.Leu660Pro (c.1979T>C), p.Arg690Cys (c.2068C>T), p.Phe735Leu (c.2205C>G), p.Asn812Ser (c.2435A>G), p.Lys892∗ (c.2674A>T), and p.Pro1025Argfs∗9 (c.3074delC) (all variants relative to transcript 1, GenBank: NM_001178065.2).