title: Global Carrier Rates of Rare Inherited Disorders Using Population Exome Sequences.
abstract: Exome sequencing has revealed the causative mutations behind numerous rare, inherited disorders, but it is challenging to find reliable epidemiological values for rare disorders. Here, I provide a genetic epidemiology method to identify the causative mutations behind rare, inherited disorders using two population exome sequences (1000 Genomes and NHLBI). I created global maps of carrier rate distribution for 18 recessive disorders in 16 diverse ethnic populations. Out of a total of 161 mutations associated with 18 recessive disorders, I detected 24 mutations in either or both exome studies. The genetic mapping revealed strong international spatial heterogeneities in the carrier patterns of the inherited disorders. I next validated this methodology by statistically evaluating the carrier rate of one well-understood disorder, sickle cell anemia (SCA). The population exome-based epidemiology of SCA [African (allele frequency (AF) = 0.0454, N = 2447), Asian (AF = 0, N = 286), European (AF = 0.000214, N = 4677), and Hispanic (AF = 0.0111, N = 362)] was not significantly different from that obtained from a clinical prevalence survey. A pair-wise proportion test revealed no significant differences between the two exome projects in terms of AF (46/48 cases; P > 0.05). I conclude that population exome-based carrier rates can form the foundation for a prospectively maintained database of use to clinical geneticists. Similar modeling methods can be applied to many inherited disorders.
authors.affiliation: Kobe University School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Fujikura
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics; D002353:Carrier State / Q000208:ethnology*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D035583:Rare Diseases / Q000208:ethnology / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*