TY - JOUR
T1 - White matter lesion progression : genome-wide search for genetic influences
AU - Hofer, Edith
AU - Cavalieri, Margherita
AU - Bis, Joshua C.
AU - DeCarli, Charles
AU - Fornage, Myriam
AU - Sigurdsson, Sigurdur
AU - Srikanth, Velandai
AU - Trompet, Stella
AU - Thomson, Russell
AU - [and fifty one others], null
PY - 2015
Y1 - 2015
N2 - Background and Purpose-White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results-A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10-8). Four loci were suggestive (P<1×10-5) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10-6); 12q13.13 (rs4761974, P=8.71×10-7); 20p12.1 (rs6135309, P=3.69×10-6); and 4p15.31 (rs7664442, P=2.26×10-6). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. Conclusions-Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.
AB - Background and Purpose-White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results-A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10-8). Four loci were suggestive (P<1×10-5) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10-6); 12q13.13 (rs4761974, P=8.71×10-7); 20p12.1 (rs6135309, P=3.69×10-6); and 4p15.31 (rs7664442, P=2.26×10-6). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. Conclusions-Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.
KW - aging
KW - cerebral small vessel diseases
KW - magnetic resonance imaging
KW - white matter lesions
UR - http://handle.uws.edu.au:8081/1959.7/uws:35988
U2 - 10.1161/STROKEAHA.115.009252
DO - 10.1161/STROKEAHA.115.009252
M3 - Article
SN - 1524-4628
SN - 0039-2499
VL - 46
SP - 3048
EP - 3057
JO - Stroke
JF - Stroke
IS - 11
ER -