NEW YORK – At least 17 sites in the human genome appear to have ties to intracranial aneurysm risk, potentially acting in combination across multiple loci with common variants, according to a new genome-wide association study by investigators at Utrecht University and elsewhere.
"We reveal a polygenic architecture and explain over half of the disease heritability," co-senior and co-corresponding author Ynte Ruigrok, a researcher at Utrecht University's brain center, and her colleagues wrote in Nature Genetics on Monday, adding that "we show a high genetic correlation between ruptured and unruptured intracranial aneurysms."
With a two-stage GWAS and meta-analysis based on genotyping profiles for nearly 10,800 individuals of European or East Asian ancestry with intracranial aneurysm and nearly 306,900 unaffected controls from the same population, the team narrowed in on 11 previously unappreciated risk loci and half a dozen loci implicated in the intracranial artery dilation disease in the past. In a series of follow-up analyses, those data helped to pinpoint biological processes that may be at play in intracranial aneurysm, along with genes that may be amenable to treatment.
"Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology," the authors reported, adding that "genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits."
For the study, the researchers began by searching for intracranial aneurysm-related variants in 7,495 cases and more than 71,900 controls from past studies done in European populations, identifying 11 suspicious loci that were subsequently validated in a meta-analysis that included thousands more cases and controls from East Asia.
Based on insights from all 10,754 intracranial aneurysm cases and 306,882 controls considered in both stages of the study — including intracranial aneurysm cases with or without ruptures — the team validated the first 11 risk loci and uncovered six more loci linked to intracranial aneurysm.
Together, these risk SNPs appeared to explain nearly 22 percent of the heritability associated with intracranial aneurysms, the investigators reported, with common variants frequently coming together to produce polygenic contributors to the condition.
The researchers went on to search for genetic overlap between intracranial artery dilations and several other conditions ranging from stroke, vascular development abnormalities, and other forms of aneurysm to smoking or high blood pressure, before using gene enrichment insights to narrow in on related genes and pathways that are known targets of existing drugs.
For example, they noted that the analyses highlighted enrichment for genes related to antihypertensive drugs, antiepileptic drugs, sex hormone-related drugs, and drugs related to ion channel function.
By bringing in additional gene expression information for follow-up gene mapping analyses, meanwhile, the team got a look at genes and biological processes that may be related to intracranial aneurysm, including endothelial cell signaling.
"Our findings represent a major advance in understanding the pathogenesis of intracranial aneurysms and an important step toward the development of effective genetic risk prediction and prevention of intracranial aneurysm development and subsequent [aneurysmal subarachnoid hemorrhage] in the future," the authors concluded.