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Family History-Based Association Method Uncovers Disease Variants

NEW YORK (GenomeWeb) – Family history of disease can be harnessed to identify disease-linked genetic loci from unaffected family members, researchers at the New York Genome Center have found.

In a study in Nature Genetics this week, they describe their genome-wide association by proxy (GWAX) approach, which uses the relatives of affected people as proxy cases and the relatives of unaffected individuals as proxy controls. The method enables genetic studies of diseases for which it is difficult to recruit patients, the researchers wrote.

They applied their method to a UK Biobank dataset to look at common diseases and found that it replicated known disease variants but also identified 17 novel variants linked to Alzheimer's disease, coronary heart diseases, and type 2 diabetes.

"There are many diseases — from autism to sudden cardiac death to dementia — where recruiting patients into studies has historically been difficult or impossible," senior author Joseph Pickrell from NYGC said in a statement. "Using this technique, we hope to run powerful genomic studies of these diseases."

While traditional case-control genetic association studies are powerful tools for teasing out genetic variants linked to disease, Pickrell and his colleagues wrote in their paper, collecting cases is time-consuming and requires researchers to decide ahead of time who is a case and who is a control. At the same time, they noted, cohort studies are often limited by insufficient numbers of cases — for example, though the UK Biobank has some 500,000 individuals in it, it only has about 55 Alzheimer's cases.

With their GWAX approach, the researchers said, they can expand that population pool — for example, the UK Biobank has some 60,000 people without Alzheimer's who said they had at least one affected parent. A person with one affected parent can be considered to have one chromosome from an affected case and one from a control, they added.

However, such an approach can be influenced by poor recall — for example, Pickrell and his colleagues noticed that women were more likely to report having an affected relative — and disease misclassification — if, for instance, type 1 diabetes and type 2 diabetes weren't distinguished on the questionnaire given to participants.

The scientists applied their GWAX approach to search for associations to a dozen common diseases within 116,196 individuals from the UK Biobank. The number of proxy cases reached from 4,627 for Parkinson's disease to 54,714 for high blood pressure. In their association testing, they uncovered 24 loci that reached genome-wide significance, a number of which replicated known associations. For instance, APOE was linked to Alzheimer's disease; LPA and CDKN21-CDNKN2B to coronary artery disease; and TCF7L2 to type 2 diabetes.

In addition, by combining their summary statistics with results from published GWAS, Pickrell and his colleagues uncovered novel risk loci for Alzheimer's disease, coronary artery disease, and type 2 diabetes.

The two new Alzheimer's loci could be traced to genes involved in immune surveillance and major histocompatibility complex class II signal transduction, which the researchers said underscored the role of innate immunity in the disease.

The coronary artery disease locus, meanwhile, was in an intron of FGD5, which regulates VEGF1, an important cytokine for the development of new vessels. And PITPNC1, which is a member of a phosphatidylinositol transfer protein family, was linked to diabetes risk.

The researchers added that their approach could be applied to other conditions for which it's difficult to recruit participants and that family history questionnaires should be included into cohort studies.