Novel Alzheimer’s disease risk genes: exhaustive investigation is paramount

Excerpt

This year marks the 10th anniversary of the publication of two genome-wide association studies (GWAS) that heralded a change in the field of complex genetics of late-onset Alzheimer’s disease (AD) [1, 2]. Until then, only APOE ɛ4 was unquestionably recognized as a genetic risk factor for AD because of its large effect on disease risk: the so-called low-hanging fruit. These two papers, however, instilled confidence in the ability of the GWAS design to also detect genetic risk loci with smaller effects on AD susceptibility [1, 2]. Since then, a widespread adoption of the GWAS approach has resulted in the identification of many AD risk genes and loci that proved to be consistent across studies. The GWAS data in turn have led to an explosion of subsequent studies of epidemiological or bioinformatic nature, e.g. correlating GWAS-identified SNPs with biomarker phenotypes, or construing information about pathophysiological pathways based on the associated SNPs, or combining alleles at associated SNPs across the genome into polygenic risk profiles. But underneath all this is the realization that GWAS typically provide indirect association signals due to the use of ‘tag’ SNPs. The still undetected genetic variants that directly modulate disease risk at GWAS loci could have a considerably different strength of effect, or uncover molecular mechanisms and pathways involved in AD risk that diverge from current knowledge. This realization has boosted in-depth molecular investigations in genes and loci identified in Alzheimer’s disease GWAS. …