Whole genome association studies in complex diseases: where do we stand?

Area of Science:

• Genetics
• Neuroscience
• Genomics

Background:

• Genome-wide association studies (GWAS) aim to identify common genetic variants linked to complex diseases.
• Success in identifying common variants has varied, with notable associations in late-onset diseases, drug response, and the major histocompatibility complex.
• Common genetic variation has explained little of the high heritability observed in neuropsychiatric traits.

Purpose of the Study:

• To evaluate the success of genome-wide association studies in identifying genetic variants associated with complex diseases.
• To highlight the contrasting findings between common variants and rare variants in neuropsychiatric genetics.
• To emphasize the potential of whole-genome sequencing for advancing the understanding of neuropsychiatric disorders.

Main Methods:

• Review of hundreds of genome-wide association studies.
• Analysis of findings related to common variants in complex diseases, late-onset diseases, drug response, and the major histocompatibility complex.
• Comparison of the utility of common variants versus rare copy number variants in neuropsychiatric genetics.

Main Results:

• Genome-wide association studies have shown varying success in identifying common variants associated with complex diseases.
• Strongest effects of common variants are observed in late-onset diseases and drug response.
• Rare copy number variants have rapidly identified genes and loci strongly associated with neuropsychiatric disorders, unlike common variation.

Conclusions:

• Common genetic variation has explained minimal heritability in neuropsychiatric traits.
• Rare variants, particularly copy number variants, offer a more promising avenue for understanding neuropsychiatric disorders.
• Whole-genome sequencing is expected to significantly advance neuropsychiatric genetics by enabling the study of rare variation.