A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly

Ho, A. J.; Stein, J. L.; Hua, X.; Lee, S.; Hibar, D. P.; Leow, A. D.; Dinov, I. D.; Toga, A. W.; Saykin, A. J.; Shen, L.; Foroud, T.; Pankratz, N.; Huentelman, M. J.; Craig, D. W.; Gerber, J. D.; Allen, A. N.; Corneveaux, J. J.; Stephan, D. A.; DeCarli, C. S.; DeChairo, B. M.; Potkin, S. G.; Jack, C. R.; Weiner, M. W.; Raji, C. A.; Lopez, O. L.; Becker, J. T.; Carmichael, O. T.; Thompson, P. M.; the Alzheimer's Disease Neuroimaging Initiative; Weiner, M.; Thal, L.; Petersen, R.; Jack, C. R.; Jagust, W.; Trojanowki, J.; Toga, A. W.; Beckett, L.; Green, R. C.; Gamst, A.; Potter, W. Z.; Montine, T.; Anders, D.; Bernstein, M.; Felmlee, J.; Fox, N.; Thompson, P.; Schuff, N.; Alexander, G.; Bandy, D.; Koeppe, R. A.; Foster, N.; Reiman, E. M.; Chen, K.; Trojanowki, J.; Shaw, L.; Lee, V. M.- Y.; Korecka, M.; Toga, A. W.; Crawford, K.; Neu, S.; Harvey, D.; Gamst, A.; Kornak, J.; Kachaturian, Z.; Frank, R.; Snyder, P. J.; Molchan, S.; Kaye, J.; Vorobik, R.; Quinn, J.; Schneider, L.; Pawluczyk, S.; Spann, B.; Fleisher, A. S.; Vanderswag, H.; Heidebrink, J. L.; Lord, J. L.; Johnson, K.; Doody, R. S.; Villanueva-Meyer, J.; Chowdhury, M.; Stern, Yaakov; Honig, L. S.; Bell, K. L.; Morris, J. C.; Mintun, M. A.; Schneider, S.; Marson, D.; Griffith, R.; Badger, B.; Grossman, H.; Tang, C.; Stern, J.; deToledo-Morrell, L.; Shah, R. C.; Bach, J.; Duara, R.; Isaacson, R.; Strauman, S.; Albert, M. S.; Pedroso, J.; Toroney, J.; Rusinek, H.; de Leon, M. J.; De Santi, S. M.; Doraiswamy, P. M.; Petrella, J. R.; Aiello, M.; Clark, C. M.; Pham, C.; Nunez, J.; Smith, C. D.; Given II, C. A.; Hardy, P.; DeKosky, S. T.; Oakley, M.; Simpson, D. M.; Ismail, M. S.; Porsteinsson, A.; McCallum, C.; Cramer, S. C.; Mulnard, R. A.; McAdams-Ortiz, C.; Diaz-Arrastia, R.; Martin-Cook, K.; DeVous, M.; Levey, A. I.; Lah, J. J.; Cellar, J. S.; Burns, J. M.; Anderson, H. S.; Laubinger, M. M.; Bartzokis, G.; Silverman, D. H. S.; Lu, P. H.; Fletcher, R.; Parfitt, F.; Johnson, H.; Farlow, M.; Herring, S.; Hake, A. M.; van Dyck, C. H.; MacAvoy, M. G.; Bifano, L. A.; Chertkow, H.; Bergman, H.; Hosein, C.; Black, S.; Graham, S.; Caldwell, C.; Feldman, H.; Assaly, M.; Hsiung, G.-Y. R.; Kertesz, A.; Rogers, J.; Trost, D.; Bernick, C.; Gitelman, D.; Johnson, N.; Mesulam, M.; Sadowsky, C.; Villena, T.; Mesner, S.; Aisen, P. S.; Johnson, K. B.; Behan, K. E.; Sperling, R. A.; Rentz, D. M.; Johnson, K. A.; Rosen, A.; Tinklenberg, J.; Ashford, W.; Sabbagh, M.; Connor, D.; Obradov, S.; Killiany, R.; Norbash, A.; Obisesan, T. O.; Jayam-Trouth, A.; Wang, P.; Auchus, A. P.; Huang, J.; Friedland, R. P.; DeCarli, C.; Fletcher, E.; Carmichael, O.; Kittur, S.; Mirje, S.; Johnson, S. C.; Borrie, M.; Lee, T.-Y.; Asthana, S.; Carlsson, C. M.; Potkin, S. G.; Highum, D.; Preda, A.; Nguyen, D.; Tariot, P. N.; Hendin, B. A.; Scharre, D. W.; Kataki, M.; Beversdorf, D. Q.; Zimmerman, E. A.; Celmins, D.; Brown, A. D.; Gandy, S.; Marenberg, M. E.; Rovner, B. W.; Pearlson, G.; Blank, K.; Anderson, K.; Saykin, A. J.; Santulli, R. B.; Pare, N.; Williamson, J. D.; Sink, K. M.; Potter, H.; Ashok Raj, B.; Giordano, A.; Ott, B. R.; Wu, C.-K.; Cohen, R.; Wilks, K. L.

A recently identified variant within the fat mass and obesity-associated (FTO) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.



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February 11, 2022