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Higher BMI, but not obesity-related genetic polymorphisms, correlates with lower structural connectivity of the reward network in a population-based study.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Obesity is of complex origin, involving genetic and neurobehavioral factors. Genetic polymorphisms may increase the risk for developing obesity by modulating dopamine-dependent behaviors, … such as reward processing. Yet, few studies have investigated the association of obesity, related genetic variants, and structural connectivity of the dopaminergic reward network. METHODS: We analyzed 347 participants (age range: 20-59 years, BMI range: 17-38 kg/m(2)) of the LIFE-Adult Study. Genotyping for the single nucleotid polymorphisms rs1558902 (FTO) and rs1800497 (near dopamine D2 receptor) was performed on a microarray. Structural connectivity of the reward network was derived from diffusion-weighted magnetic resonance imaging at 3 T using deterministic tractography of Freesurfer-derived regions of interest. Using graph metrics, we extracted summary measures of clustering coefficient and connectivity strength between frontal and striatal brain regions. We used linear models to test the association of BMI, risk alleles of both variants, and reward network connectivity. RESULTS: Higher BMI was significantly associated with lower connectivity strength for number of streamlines (beta = -0.0025, 95%-C.I.: [-0.004, -0.0008], p = 0.0042), and, to lesser degree, fractional anisotropy (beta = -0.0009, 95%-C.I. [-0.0016, -0.00008], p = 0.031), but not clustering coefficient. Strongest associations were found for left putamen, right accumbens, and right lateral orbitofrontal cortex. As expected, the polymorphism rs1558902 in FTO was associated with higher BMI (F = 6.9, p < 0.001). None of the genetic variants was associated with reward network structural connectivity. CONCLUSIONS: Here, we provide evidence that higher BMI correlates with lower reward network structural connectivity. This result is in line with previous findings of obesity-related decline in white matter microstructure. We did not observe an association of variants in FTO or near DRD2 receptor with reward network structural connectivity in this population-based cohort with a wide range of BMI and age. Future research should further investigate the link between genetics, obesity and fronto-striatal structural connectivity.

Authors: F. Beyer, R. Zhang, M. Scholz, K. Wirkner, M. Loeffler, M. Stumvoll, A. Villringer, A. V. Witte

Date Published: 25th Oct 2020

Publication Type: Journal article

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining … association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Authors: Laura Fachal, Hugues Aschard, Jonathan Beesley, Daniel R. Barnes, Jamie Allen, Siddhartha Kar, Karen A. Pooley, Joe Dennis, Kyriaki Michailidou, Constance Turman, Penny Soucy, Audrey Lemaçon, Michael Lush, Jonathan P. Tyrer, Maya Ghoussaini, Mahdi Moradi Marjaneh, Xia Jiang, Simona Agata, Kristiina Aittomäki, M. Rosario Alonso, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Bernd Auber, Paul L. Auer, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Alicia Beeghly-Fadiel, Javier Benitez, Marina Bermisheva, Katarzyna Białkowska, Amie M. Blanco, Carl Blomqvist, William Blot, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Ake Borg, Kristin Bosse, Hiltrud Brauch, Hermann Brenner, Ignacio Briceno, Ian W. Brock, Angela Brooks-Wilson, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Qiuyin Cai, Trinidad Caldés, Maria A. Caligo, Nicola J. Camp, Ian Campbell, Federico Canzian, Jason S. Carroll, Brian D. Carter, Jose E. Castelao, Jocelyne Chiquette, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, J. Margriet Collée, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Miguel de La Hoya, Peter Devilee, Orland Diez, Yuan Chun Ding, Gillian S. Dite, Susan M. Domchek, Thilo Dörk, Isabel Dos-Santos-Silva, Arnaud Droit, Stéphane Dubois, Martine Dumont, Mercedes Duran, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Olivia Fletcher, Giuseppe Floris, Henrik Flyger, Lenka Foretova, William D. Foulkes, Eitan Friedman, Lin Fritschi, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Gaetana Gambino, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Maria Grazia Tibiletti, Mark H. Greene, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Jaana M. Hartikainen, Mikael Hartman, Wei He, Catherine S. Healey, Bernadette A. M. Heemskerk-Gerritsen, Jane Heyworth, Peter Hillemanns, Frans B. L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, John L. Hopper, Anthony Howell, Guanmengqian Huang, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Motoki Iwasaki, Agnes Jager, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Daehee Kang, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Michael J. Kerin, Elza Khusnutdinova, Johanna I. Kiiski, Judy Kirk, Cari M. Kitahara, Yon-Dschun Ko, Irene Konstantopoulou, Veli-Matti Kosma, Stella Koutros, Katerina Kubelka-Sabit, Ava Kwong, Kyriacos Kyriacou, Yael Laitman, Diether Lambrechts, Eunjung Lee, Goska Leslie, Jenny Lester, Fabienne Lesueur, Annika Lindblom, Wing-Yee Lo, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Jan Lubiński, Robert J. MacInnis, Tom Maishman, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Keitaro Matsuo, Tabea Maurer, Dimitrios Mavroudis, Rebecca Mayes, Lesley McGuffog, Catriona McLean, Noura Mebirouk, Alfons Meindl, Austin Miller, Nicola Miller, Marco Montagna, Fernando Moreno, Kenneth Muir, Anna Marie Mulligan, Victor M. Muñoz-Garzon, Taru A. Muranen, Steven A. Narod, Rami Nassir, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Finn C. Nielsen, Liene Nikitina-Zake, Aaron Norman, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Nick Orr, Ana Osorio, V. Shane Pankratz, Janos Papp, Sue K. Park, Tjoung-Won Park-Simon, Michael T. Parsons, James Paul, Inge Sokilde Pedersen, Bernard Peissel, Beth Peshkin, Paolo Peterlongo, Julian Peto, Dijana Plaseska-Karanfilska, Karolina Prajzendanc, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Miquel Angel Pujana, Katri Pylkäs, Paolo Radice, Susan J. Ramus, Johanna Rantala, Rohini Rau-Murthy, Gad Rennert, Harvey A. Risch, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Estela Sánchez-Herrero, Dale P. Sandler, Marta Santamariña, Christobel Saunders, Elinor J. Sawyer, Maren T. Scheuner, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Ben Schöttker, Peter Schürmann, Christopher Scott, Rodney J. Scott, Leigha Senter, Caroline M. Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xiao-Ou Shu, Christian F. Singer, Thomas P. Slavin, Snezhana Smichkoska, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony J. Swerdlow, Rulla M. Tamimi, Yen Yen Tan, William J. Tapper, Jack A. Taylor, Manuel R. Teixeira, Maria Tengström, Soo Hwang Teo, Mary Beth Terry, Alex Teulé, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Rob A. E. M. Tollenaar, Ian Tomlinson, Diana Torres, Gabriela Torres-Mejía, Melissa A. Troester, Thérèse Truong, Nadine Tung, Maria Tzardi, Hans-Ulrich Ulmer, Celine M. Vachon, Christi J. van Asperen, Lizet E. van der Kolk, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Joseph Vijai, Maartje J. Vogel, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Hans Wildiers, Robert Winqvist, Alicja Wolk, Anna H. Wu, Drakoulis Yannoukakos, Yan Zhang, Wei Zheng, David Hunter, Paul D. P. Pharoah, Jenny Chang-Claude, Montserrat García-Closas, Marjanka K. Schmidt, Roger L. Milne, Vessela N. Kristensen, Juliet D. French, Stacey L. Edwards, Antonis C. Antoniou, Georgia Chenevix-Trench, Jacques Simard, Douglas F. Easton, Peter Kraft, Alison M. Dunning

Date Published: 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Genome-wide association study of germline variants and breast cancer-specific mortality
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS Meta-analyses included summary estimates …tes based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS We did not find any variant associated with breast cancer-specific mortality at P \textless 5 \times 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 \times 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 \times 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS We uncovered germline variants on chromosome 7 at BFDP \textless 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Authors: Maria Escala-Garcia, Qi Guo, Thilo Dörk, Sander Canisius, Renske Keeman, Joe Dennis, Jonathan Beesley, Julie Lecarpentier, Manjeet K. Bolla, Qin Wang, Jean Abraham, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Paul L. Auer, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Bram Boeckx, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Adam Brentnall, Louise Brinton, Per Broberg, Ian W. Brock, Sara Y. Brucker, Barbara Burwinkel, Carlos Caldas, Trinidad Caldés, Daniele Campa, Federico Canzian, Angel Carracedo, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Ting-Yuan David Cheng, Suet-Feung Chin, Christine L. Clarke, Emilie Cordina-Duverger, Fergus J. Couch, David G. Cox, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Janet A. Dunn, Alison M. Dunning, Lorraine Durcan, Miriam Dwek, Helena M. Earl, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Jonine Figueroa, Dieter Flesch-Janys, Henrik Flyger, Marike Gabrielson, Manuela Gago-Dominguez, Eva Galle, Susan M. Gapstur, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Angela George, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, David E. Goldgar, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Susan Hankinson, Elaine F. Harkness, Patricia A. Harrington, Steven N. Hart, Jaana M. Hartikainen, Alexander Hein, Peter Hillemanns, Louise Hiller, Bernd Holleczek, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Wolfgang Janni, Esther M. John, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Maria Kabisch, Katarzyna Kaczmarek, Michael J. Kerin, Sofia Khan, Elza Khusnutdinova, Johanna I. Kiiski, Cari M. Kitahara, Julia A. Knight, Yon-Dschun Ko, Linetta B. Koppert, Veli-Matti Kosma, Peter Kraft, Vessela N. Kristensen, Ute Krüger, Tabea Kühl, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Flavio Lejbkowicz, Lian Li, Annika Lindblom, Sara Lindström, Martha Linet, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jan Lubiński, Michael P. Lux, Robert J. MacInnis, Melanie Maierthaler, Tom Maishman, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Dimitrios Mavroudis, Catriona McLean, Alfons Meindl, Pooja Middha, Nicola Miller, Roger L. Milne, Fernando Moreno, Anna Marie Mulligan, Claire Mulot, Rami Nassir, Susan L. Neuhausen, William T. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Håkan Olsson, Nick Orr, V. Shane Pankratz, Tjoung-Won Park-Simon, Jose I. A. Perez, Clara Pérez-Barrios, Paolo Peterlongo, Christos Petridis, Mila Pinchev, Karoliona Prajzendanc, Ross Prentice, Nadege Presneau, Darya Prokofieva, Katri Pylkäs, Brigitte Rack, Paolo Radice, Dhanya Ramachandran, Gadi Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Rebecca Roylance, Emmanouil Saloustros, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Lukas Schwentner, Rodney J. Scott, Christopher Scott, Caroline Seynaeve, Mitul Shah, Jacques Simard, Ann Smeets, Christof Sohn, Melissa C. Southey, Anthony J. Swerdlow, Aline Talhouk, Rulla M. Tamimi, William J. Tapper, Manuel R. Teixeira, Maria Tengström, Mary Beth Terry, Kathrin Thöne, Rob A. E. M. Tollenaar, Ian Tomlinson, Diana Torres, Thérèse Truong, Constance Turman, Clare Turnbull, Hans-Ulrich Ulmer, Michael Untch, Celine Vachon, Christi J. van Asperen, Ans M. W. van den Ouweland, Elke M. van Veen, Camilla Wendt, Alice S. Whittemore, Walter Willett, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Yan Zhang, Douglas F. Easton, Peter A. Fasching, Heli Nevanlinna, Diana M. Eccles, Paul D. P. Pharoah, Marjanka K. Schmidt

Date Published: 1st Mar 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for … prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

Authors: Nasim Mavaddat, Kyriaki Michailidou, Joe Dennis, Michael Lush, Laura Fachal, Andrew Lee, Jonathan P. Tyrer, Ting-Huei Chen, Qin Wang, Manjeet K. Bolla, Xin Yang, Muriel A. Adank, Thomas Ahearn, Kristiina Aittomäki, Jamie Allen, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Päivi Auvinen, Myrto Barrdahl, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Michael Bremer, Hermann Brenner, Adam Brentnall, Ian W. Brock, Angela Brooks-Wilson, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Daniele Campa, Brian D. Carter, Jose E. Castelao, Stephen J. Chanock, Rowan Chlebowski, Hans Christiansen, Christine L. Clarke, J. Margriet Collée, Emilie Cordina-Duverger, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Isabel Dos-Santos-Silva, Martine Dumont, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Asta Försti, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Irina R. Gilyazova, Gord Glendon, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Susan E. Hankinson, Elaine F. Harkness, Steven N. Hart, Wei He, Alexander Hein, Jane Heyworth, Peter Hillemanns, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Milena Jakimovska, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Katarzyna Kaczmarek, Vesa Kataja, Renske Keeman, Michael J. Kerin, Elza Khusnutdinova, Johanna I. Kiiski, Julia A. Knight, Yon-Dschun Ko, Veli-Matti Kosma, Stella Koutros, Vessela N. Kristensen, Ute Krüger, Tabea Kühl, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Flavio Lejbkowicz, Jenna Lilyquist, Annika Lindblom, Sara Lindström, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jirong Long, Jan Lubiński, Michael P. Lux, Robert J. MacInnis, Tom Maishman, Enes Makalic, Ivana Maleva Kostovska, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Maria Elena Martinez, Dimitrios Mavroudis, Catriona McLean, Alfons Meindl, Usha Menon, Pooja Middha, Nicola Miller, Fernando Moreno, Anna Marie Mulligan, Claire Mulot, Victor M. Muñoz-Garzon, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Kenneth Offit, Janet E. Olson, Håkan Olsson, Nick Orr, V. Shane Pankratz, Tjoung-Won Park-Simon, Jose I. A. Perez, Clara Pérez-Barrios, Paolo Peterlongo, Julian Peto, Mila Pinchev, Dijana Plaseska-Karanfilska, Eric C. Polley, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Kristen Purrington, Katri Pylkäs, Brigitte Rack, Paolo Radice, Rohini Rau-Murthy, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Mark Robson, Atocha Romero, Kathryn J. Ruddy, Matthias Ruebner, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Peter Schürmann, Lukas Schwentner, Christopher Scott, Rodney J. Scott, Caroline Seynaeve, Mitul Shah, Mark E. Sherman, Martha J. Shrubsole, Xiao-Ou Shu, Susan Slager, Ann Smeets, Christof Sohn, Penny Soucy, Melissa C. Southey, John J. Spinelli, Christa Stegmaier, Jennifer Stone, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Kathrin Thöne, Rob A. E. M. Tollenaar, Ian Tomlinson, Thérèse Truong, Maria Tzardi, Hans-Ulrich Ulmer, Michael Untch, Celine M. Vachon, Elke M. van Veen, Joseph Vijai, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Walter Willett, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Drakoulis Yannoukakos, Yan Zhang, Wei Zheng, Argyrios Ziogas, Alison M. Dunning, Deborah J. Thompson, Georgia Chenevix-Trench, Jenny Chang-Claude, Marjanka K. Schmidt, Per Hall, Roger L. Milne, Paul D. P. Pharoah, Antonis C. Antoniou, Nilanjan Chatterjee, Peter Kraft, Montserrat García-Closas, Jacques Simard, Douglas F. Easton

Date Published: 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

ASSOCIATION OF HIPPOCAMPAL VOLUMES WITH COGNITIVE TASKS IN A LARGE POPULATION-BASED COHORT
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Background: Hippocampal volume, assessed via high-resolution MRI, is associated with memory and visuospatial performance in humans (Squire, 2004) and specifically prone to develop atrophy with age … (Apostolova,2015). This process has been linked to neurodegenerative diseases, such as Alzheimer’s disease (Apostolova,2015) and a decline of cognitive functions (Bruno,2016). However, due to differences in study-design and characteristics certain heterogeneity in results remains, in particular considering subfieldspecific effects (deFlores,2015). Therefore, we aim to determine the association of volumes of the whole hippocampus and its subfields on cognition in a large population-based cohort. Methods: Subjects: 1956 healthy participants from the Leipzig Research-Center-for-Civilization-Disease, aged 19-82years with MRI and neuropsychological tests (mean-age=57.61,±15.08SD). Exclusion: stroke, major-brain-pathologies, central-nervous-medication. Independent Variables: Volume of hippocampus and its subfields (CornuAmmonis1, 2-3, 4-DentateGyrus,(Pre-)subiculum). Dependent Variables: Verbal word-list learning, verbal-fluency, TrailMakingTask-(TMT)-A&B. Covariates: sex, age, years-of-education, total grey-mattervolume Image Analysis on high-resolution T1-images assessed at 3T. Hippocampal volumes were estimated using automatic segmentation analysis implemented in FreeSurfer (www.freesurfer.net). Statistical Analysis: Independent and dependent variables were first entered into Pearson Correlations. Variables with a correlation coefficient of r>0.1 were entered into multiple linear-regressions and adjusted for potential confounding(forward inclusion-model). Results: According to bivariate correlations, better performance in verbal-learning, verbal-fluency and TMT-A&B correlated moderately with larger whole-hippocampal volume and the volumes of all subfields(all |r|>0.102, all p0.046, all p0.5). Conclusions: Using a large cross-sectional cohort of healthy adults we found that volumes of the whole-hippocampus and subfields covering the CA4/dentate-gyrus region were weakly, yet specifically associated with verbal-learning and spatial processing-speed. Our preliminary results are in line with previous studies presuming a differential involvement of the hippocampus in tasks of verbal-learning and spatial processing (Oosterman,2010). Upcoming analyses implementing parcellation along the anteriorposterior- axis and random-effect-models might help to further disentangle these effects.

Authors: S. Huhn, R. Zhang, Frauke Beyer, L. Lampe, T. Luck, S. G. Riedel-Heller, M. L. Schroeter, Markus Löffler, M. Stumvoll, A. Villringer, A. V. Witte

Date Published: 1st Jul 2017

Publication Type: Not specified

Human Diseases: cognitive disorder, dementia

Diabetes and hypertension contribute to normal-appearing white matter microstructural variability in the brain
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Background and objectives: Obesity has been associated with increased risk of dementia. Grey and white matter (WM) of the brain are commonly used as biomarkers for early detection of dementia. However, … considering WM, available neuroimaging studies had mainly small sample size and yielded less conclusive results (Kullmann et al., 2015). Recently, a positive correlation between obesity and fractional anisotropy (FA) in a middle age group was reported (Birdsill et al. 2017). Furthermore, obesity is related to many medical problems such as diabetes and hypertension. Diabetes and hypertension were found to be correlated with brain structures independently (de Leeuw et al., 2002; Weinstein et al., 2015). Yet, studies rarely investigated non-lesion WM microstructure and its association with diabetes and blood pressure. Therefore we aim to investigate the relation between abdominal obesity, diabetes, blood pressure and WM microstructural variability in a large cohort of community-dwelling healthy adults. Methods: The sample included dementia-free participants (mean age 55 ± 16 years; 50.7% women) of the LIFE cohort with brain MRI scans (n = 1255). WM microstructure was measured with diffusion tensor imaging (DTI). Mean FA was derived from the individual WM skeleton processed by tract-based-spatial-statistic method. Linear regression models were used to assess the relationships between diabetes, blood pressure, waist to hip ratio (WHR) and DTI parameters. Adjustments were made for age, sex, education and Apoe4. Results: The preliminary result indicated diabetes, systolic blood pressure and WHR were independently associated with lower FA, and diabetes explained the most variance besides age. Subgroup analysis revealed both systolic blood pressure and WHR were negatively associated with mean FA in the non-diabetes group (n=1101). Conclusions: The preliminary result of our study indicates that diabetes accelerated brain aging on directional diffusion of WM. Abdominal fat and blood pressure were associated with WM variabilities independently from age, sex and diabetes. With subsequent analysis of additional DTI measures, blood parameters, WM hyperintensity maps and voxel-based microstructural WM “integrity”, we aim to further characterize the associations between obesity, diabetes, blood pressure and WM microstructure. This will contribute to the existing literature and help to disentangle the underlying mechanism.

Authors: Rui Zhang, Frauke Beyer, L. Lampe, T. Luck, S. G. Riedel-Heller, M. Stumvoll, Markus Löffler, M. L. Schroeter, A. Villringer, A. V. Witte

Date Published: 2017

Publication Type: Not specified

Human Diseases: diabetes mellitus, obesity, hypertension

Obesity is Associated with White Matter Changes and Cognitions among Healthy Elderly
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Midlife obesity has often been associated with accelerated cognitive decline during aging. Obesity leads to changes in multiple physiological factors that could impact neuronal tissue. Numerous studies … have linked obesity and higher body mass index (BMI) with differences in cognitive functions and brain structure, including total brain volume, regional gray matter volume and white matter (WM) microstructure. However, regarding to WM, the available neuroimaging studies incorporated mainly small sample sizes that yielded less conclusive results. Thus, we investigated the association of obesity, measured using BMI and waist to hip ratio (WHR), with changes in WM microstructure, as well as variance in cognitive test scores in a large cohort of community-dwelling healthy individuals older than 60 years.

Authors: Rui Zhang, L. Lampe, Frauke Beyer, Sebastian Huhn, S. K. Masouleh, T. Luck, S. G. Riedel-Heller, Markus Löffler, M. L. Schroeter

Date Published: 28th Nov 2016

Publication Type: Not specified

Human Diseases: obesity

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