Researchers have pinpointed new genetic variants that associate with endophenotypes of Alzheimer’s disease. In the January 16 Neurology, scientists led by Sudha Seshadri at Boston University report chromosomal loci that associate with cerebral and hippocampal atrophy. In addition, rare variants at two genes, FCHO2 and SOCS7, reached statistical significance for cerebral volume. Alzforum first covered this data when first author Chloé Sarnowski presented it at the 2017 Alzheimer's Association International Conference in London (Aug 2017 conference news).

Previously, genome-wide association studies conducted by Seshadri and others revealed links between common genetic variants and brain imaging phenotypes (see, for example, Bis et al., 2012; Traylor et al., 2016). “Here we used whole-genome sequencing, which allows us to find many more variants, including rare ones,” Sarnowski told Alzforum.

The authors matched MRI and genomic data from the Framingham Heart Study with whole-genome sequencing (WGS) data collected as part of the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine program (TOPMed). They correlated single-nucleotide variants (SNVs) with total cerebral volume in 2,180 people, hippocampal volume in 2,170, and white-matter hyperintensities in 1,667 people. Mean ages were 60 to 62 years.

In addition to identifying new loci on chromosome 1p21 for cerebral volume, and on 16q23 for hippocampal volume, Sarnowski confirmed previously identified associations in 12q24 for hippocampal volume, and in 17q25 for white-matter hyperintensities. To increase the power of the search and detect gene-based associations, she combined rare variants within the same gene to uncover hits that could be missed when individual SNV effects failed to reach statistical significance. Sarnowski also used a “sliding-window” approach in which she combined hits within 4 kb gene regions to look for associations. This filter boosts detection power when only one region in a gene associates with a phenotype. A third filter selected SNVs most likely to affect the function of the encoded protein, such as missense or loss-of-function mutations.

Together, the filters revealed 10 potential new genes. Interestingly, GBA3, a Parkinson’s disease gene, associated with white-matter hyperintensities, and UNC5D, previously linked to Alzheimer’s, with cerebral volume, though these associations did not cross the threshold for statistical significance. Significant associations emerged between cerebral volume and FCHO2, a gene involved in endocytosis, and SOCS7, an anti-inflammatory gene.

Sarnowski plans to replicate the findings. The TOPMed dataset now includes more than 100,000 genomes.—Marina Chicurel


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News Citations

  1. Searching for New AD Risk Variants? Move Beyond GWAS

Paper Citations

  1. . Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nat Genet. 2012;44(5):545-51. PubMed.
  2. . Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke. Neurology. 2016 Jan 12;86(2):146-53. Epub 2015 Dec 16 PubMed.

Further Reading

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Primary Papers

  1. . Whole genome sequence analyses of brain imaging measures in the Framingham Study. Neurology. 2018 Jan 16;90(3):e188-e196. Epub 2017 Dec 27 PubMed.