There is a variable contribution of rare variation of strong effect. This tends to be larger for early onset, severe disorders and lesser for disorders with normal-range developmental trajectories and adult onset (Figure 2a). However, even for psychiatric disorders with many proven examples of rare variants of strong effect (e.g., intellectual disability or early-onset Alzheimer’s disease), there is always a contribution of common variation. Rare variant studies have proven more difficult than anticipated: to confidently identify rare variants of strong effect in typical clinical samples requires very large sample sizes, perhaps as many as ~100K cases (32). The protein-coding parts of the genome are replete with inconsequential variation, and current ways to predict functional consequences are imprecise (33). There is a lot of noise, and the signal is sparser and weaker than anticipated.
