Fifth, this argument is counter to best practices in human genetics that demand rigorous significance thresholds and replication. 51–55 For GWAS, the 5x10−8 threshold is nearly universally accepted. For rare variants of strong effect, a recent Nature paper summarized the recommendations of an NHGRI working group: 56 (a) “we emphasize the critical primacy of robust statistical genetic support for the implication of new genes, which may then be supplemented with ancillary experimental or informatic evidence supporting a mechanistic role”; (b) “Just as for genome-wide association studies of common variants, replication of newly implicated disease genes in independent families or population cohorts is critical supporting evidence, and in most cases essential for a novel gene to be regarded as convincingly implicated in disease”; and (c) “Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease”.
