Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2
Interview conducted by Michelle Christina Johansen, MD

Dr. Johansen: Dr. Mitchell, could you summarize for us the major findings of your recent article in Stroke?
Dr. Mitchell: Our study focused on young onset stroke since stroke occurring at younger ages may have a stronger genetic component. We performed a large genome-wide association study, or GWAS, that included 5,500 ischemic stroke cases and over 30,000 controls amassed from 8 different studies. We identified a DNA variant that was significantly associated with stroke, with the risk allele increasing stroke risk in young people by about 40%. This variant is near a gene called HABP2, which encodes an enzyme involved in the regulation of the clotting cascade. In an independent population from Sweden, we then found this variant also to be associated with enzyme levels.

Our study also suggests that the effects at the HABP2 locus may be specific to (or at least more pronounced in) early onset stroke because the association was largely absent in METASTROKE studies, a very large consortium that includes predominantly older stroke cases.

Dr. Johansen: Why do you feel that there is a stronger genetic component for stroke in the young?
Dr. Mitchell: It is clear from family and twin studies that stroke aggregates in families. The best available evidence suggests that stroke at younger ages has an even stronger genetic basis than stroke occurring at older ages. For example, younger stroke cases more often report a parental history of stroke than older stroke cases.

One unanswered question is whether the stronger familial aggregation observed in early- compared to later-onset stroke is due to differences in the in the distribution of stroke subtypes at different ages. For example, large artery and small vessel stroke are more prominent at older compared to younger ages, while stroke due to other determined etiologies are more common at younger ages. It is thus possible that the enrichment of stroke with some of these other causes accounts for the stronger genetic component for stroke in the young.

Dr. Johansen: How did you reach 60 years old as the parameter for stroke in the young?
Dr. Mitchell: We wanted to differentiate stroke occurring in young and middle age vs that occurring in older ages. Our decision to use a threshold of 60 years for early onset stroke, instead of say 50 or 55 years, was in part a practical one so that we would have a large enough sample for our study.

Dr. Johansen: Why do you feel that you were unable to find any subtype specific stroke susceptibility loci in your cohort?
Dr. Mitchell: We did perform additional analyses to determine if the stroke-associated variant we detected in HABP2 was associated with particular subtypes. In this analysis, we found the variant to be associated with each of the three major stroke subtypes, cardioembolic stroke, large artery atherosclerotic stroke, and small vessel occlusion. However, one major caveat is that the sample sizes were much smaller in these subtype-specific analyses, so we cannot be fully confident in these results. We are aware that the 7 or so variants robustly associated with ischemic stroke in very large GWAS studies all seem to be subtype-specific. Whether this is also true for the variant in HABP2 is premature to say.

Dr. Johansen: What do you feel is the biggest strength of your study?
Dr. Mitchell: I think our study has three major strengths. First, our study included a very large number of early onset cases. Second, not only did we detect a statistically significant association of this variant with stroke, but in an independent population of non-stroke cases, we also found this variant to be associated with circulating plasma levels of factor VII-activating protease levels, the product of this gene. Third, because the association was largely absent in the METASTROKE Consortium, we are able to conclude that the locus is probably specific to younger onset cases.

Dr. Johansen: How do you foresee the findings of this study influencing further research?
Dr. Mitchell: First, these results reinforce the heterogeneous nature of stroke as HABP2 does not appear to be associated with common forms of late onset stroke. Second, these results suggest the need to look comprehensively at genetic determinants of thrombosis and coagulation in early onset ischemic stroke. A better understanding the pathogenesis of early onset stroke may improve strategies to prevent recurrences. In addition, the pathways involved may have relevance also to some forms of older onset stroke.

Dr. Johansen: There are some naysayers who challenge the clinical value of GWAS stroke studies. Would you like to respond to this criticism?
Dr. Mitchell: I don’t believe that GWAs studies were ever intended to provide clinical or predictive value for most complex diseases. Most loci identified through GWAs have relatively small effect sizes and they do not do a very good job, even in aggregate, of predicting disease, although there are a few exceptions, such as for age-related macular degeneration. But GWAS have been enormously important in identifying variants and genes associated with a large number of diseases. This understanding is essential for development of new drugs targeting novel mechanisms.