The modest size of genetic effects detected so far confirms the multifactorial aetiology of these conditions and suggests that complex diseases will require substantially greater research effort to detect additional genetic influences. Near-term approaches for finding missing heritability on which there seems to be wide agreement include: targeted or whole-genome sequencing in people with extreme phenotypes, especially those with available family members and consent for recontact and iterative phenotyping; use of expanded reference panels of genomic variation such as 1,000 Genomes to enhance coverage of existing and future GWAS; mining of existing GWAS for associations with structural variants and evidence of gene–gene interactions; improved methods for detection of CNVs and other structural variants, applied to large, well-phenotyped groups and families; and expansion of sample sizes for numerous complex diseases through larger individual studies and meta-analyses, including people of non-European ancestry.
