20 April 2012. Challenging as it is to find risk genes for complex disorders, the task intensifies for Alzheimer’s and other diseases that appear in old age, since people can die of so many other causes before showing signs of the disease. To get around this problem, scientists have begun hunting for genes influencing brain features that associate with disease risk but can be measured years before symptoms crop up. Several international teams have pooled genomic data and brain scans from thousands of people, and report several new loci linked to hippocampal and intracranial volumes in four papers posted online April 15 in Nature Genetics. Besides demonstrating the power of collaborative research with massive datasets, the findings point toward potential new therapeutic targets for AD and other brain disorders.

The current research was initiated by two multi-national consortia. CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) began as a collection of U.S. and European elderly cohorts for genomewide association studies in cardiovascular health, and later grew to include neuroimaging. Sudha Seshadri at Boston University, Massachusetts, leads the CHARGE neurology subgroup and was a principal investigator on the new work. ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) focuses on brain disorders but looks across the lifespan, so includes a wider spectrum—from healthy young adults to seniors with dementia. Paul Thompson of the University of California, Los Angeles, headed the ENIGMA team.

Each consortium scoured its participants’ genomes for single nucleotide polymorphisms (SNPs) associating with brain measures on magnetic resonance imaging (MRI) scans, then sent their top hits to the other consortium, and additional researchers, for validation. No SNP associated with total brain volume, but several gene variants tracked with hippocampal size or intracranial volume, which measures total space within the skull, irrespective of brain size. The hippocampus shrinks with normal aging, and more dramatically before and during AD. Intracranial volume is also down in AD patients (Wolf et al., 2004), though less strikingly.

The CHARGE team—led by Seshadri, along with Charles DeCarli of the University of California, Davis, and M. Arfan Ikram of Erasmus Medical Center in Rotterdam, the Netherlands—analyzed genotyping and MRI data from 9,232 cognitively intact seniors. They found two loci on chromosome 12 that correlate with hippocampal volume. The stronger hit was a 12q24 SNP between genes HRK and FBXW8, which encode proteins that regulate apoptosis and ubiquitination, respectively. The second locus, at 12q14, included two SNPs—one in the intron of an enzyme (MSRB3) involved with oxidative stress, the other between genes encoding a Wnt signaling protein (WIF1) and transforming growth factor-β antagonist (LEMD3). People with one of these SNPs had, on average, smaller hippocampi equivalent to an extra four to five years of aging.

The ENIGMA effort—headed by Thompson and first author Jason Stein of University of California, Los Angeles—also turned up a chromosome 12q24 SNP that associates with reduced hippocampal volume. This polymorphism lands in between genes, the closest being one called TESC, which is expressed in the hippocampus and influences brain development. Moreover, the 12q24 variant not only knocks off the equivalent of three years of brain aging, it also correlates with TESC expression. The latter was demonstrated by collaborators in London who measured TESC levels in hippocampal tissue from epilepsy patients.

The other major hit from ENIGMA—which analyzed more than 21,000 people—was a chromosome 12q14 polymorphism that associates with greater intracranial volume and brain size. Found near the 3’ untranslated region of HMGA2, a protein important for stem cell renewal, this SNP seems to influence not just brain size but also function. “By having a single switch from a T to C, overall brain size was boosted about 0.5 percent—and if you had two C alleles, it would go up by 1 percent,” Thompson told Alzforum. C carriers also had higher IQ scores, by about 1.3 points per allele. A SNP near HGM2A also came up as a top hit in an independent search for genes associated with infant head circumference, also reported this week in Nature Genetics. Greater head growth during the first year of life has been linked to higher childhood IQ (see Gale et al., 2006).

The infant study—a meta-analysis of seven genomewide association studies involving 10,768 people in pregnancy and/or birth cohorts—came up with two additional hits. One SNP, at 12q24, falls within a gene implicated in cancer (SBNO1). The second lies within the chromosome 17q21 inversion that includes MAPT and GRN. These genes encode tau and granulin, which have mutations linked to neurodegenerative diseases, including AD and frontotemporal lobar dementia.

The CHARGE study also picked up a signal in 17q21, which correlated with intracranial volume in healthy elderly. Taken together, the infant study and CHARGE data suggest that genes in this chromosome 17 region might link early brain growth with neurological disease, such as Alzheimer’s, in adulthood. However, such a direct relationship cannot be established at present, suggested H. Rob Taal of Erasmus Medical Center in an e-mail to Alzforum. The findings “give clues for further research to investigate exact underlying consequences of these associations, investigate if specific parts of the brain or brain development are involved, and how this affects neurodevelopment in early and later life,” noted Taal, who was first author on the infant study (see full comment below). A second CHARGE SNP linked to intracranial volume came up in a known height-associated locus on chromosome 6q22.

Though most were replicated in the other consortium, the key SNPs from ENIGMA did not initially come up as major hits in CHARGE, and vice versa. This could have stemmed from differences in the cohorts (e.g., ENIGMA included people with dementia and psychiatric disease, as well as younger individuals, whereas CHARGE was all dementia-free elderly) as well as procedures. For example, ENIGMA used automated tools (FreeSurfer) to calculate intracranial volume, while CHARGE used mostly hand-traced methods, DeCarli noted. Seshadri told Alzforum that a combined meta-analysis of ENIGMA and CHARGE data is in the works.

The SNPs reported in the current papers have not come up in previous AD/dementia GWAS. However, “we will likely see a signal with some of these SNPs once the AD sample size is large enough,” Seshadri told ARF. However, some gene variants may associate with hippocampal volume through processes related to development or vascular injury, and may show only weak or no association with AD risk, she noted. In the CHARGE study, four AD risk genes (APOE, BIN1, MS4A4E, and TOMM40) showed “nominal association” with smaller hippocampal volume; others did not. Again, this was not entirely unexpected, Seshadri said. As the CHARGE analysis excluded people with clinical stroke or AD, she noted, “we were underpowered to find association with AD genes.” —Esther Landhuis

Reference:

Stein JL et al. Identification of common variants associated with human hippocampal and intracranial volumes. Nat Genet. 2012 Apr 15. Abstract

Bis JC et al. Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nat Genet. 2012 Apr 15. Abstract

Ikram MA et al. Common variants at 6q22 and 17q21 are associated with intracranial volume. Nat Genet. 2012 Apr 15. Abstract

Taal HR et al. Common variants at 12q15 and 12q24 are associated with infant head circumference. Nat Genet. 2012 Apr 15. Abstract