in candidate gene studies suggest that we have many more study targets with good statistical evidence besides the three most replicable GWAS loci. The fourth “immature” approach is also hypothesis driven and has verified the importance of rare variants in ND genetics.133-135, 138 Besides the demonstrated aggregate effects of rare variants in 12 genetic loci implicated in previous studies, biological candidates showing equivocal or no association beforehand were found to be significantly associated with ND-related phenotypes, such as CHRNB2, CHRNA9, CHRNA2, NRXN2, NRXN3, and CDH13, among which CHRNA9 and NRXN2 are within linkage regions.34, 141 Thus, we believe whole-exome and whole-genome sequencing studies focusing on rare variants, as the third unbiased experimental approach, will reveal new susceptibility genes/variants and further dissect the existing targets.
