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7 results on '"Daly, M. (Mark)"'

1. Cohort profile:SUPER-Finland – the Finnish study for hereditary mechanisms of psychotic disorders

Author

Lähteenvuo, M. (Markku), Ahola-Olli, A. (Ari), Suokas, K. (Kimmo), Holm, M. (Minna), Misiewicz, Z. (Zuzanna), Jukuri, T. (Tuomas), Männynsalo, T. (Teemu), Wegelius, A. (Asko), Haaki, W. (Willehard), Kajanne, R. (Risto), Kyttälä, A. (Aija), Tuulio-Henriksson, A. (Annamari), Lahdensuo, K. (Kaisla), Häkkinen, K. (Katja), Hietala, J. (Jarmo), Paunio, T. (Tiina), Niemi-Pynttäri, J. (Jussi), Kieseppä, T. (Tuula), Veijola, J. (Juha), Lönnqvist, J. (Jouko), Isometsä, E. (Erkki), Kampman, O. (Olli), Tiihonen, J. (Jari), Hyman, S. (Steven), Neale, B. (Benjamin), Daly, M. (Mark), Suvisaari, J. (Jaana), Palotie, A. (Aarno), Lähteenvuo, M. (Markku), Ahola-Olli, A. (Ari), Suokas, K. (Kimmo), Holm, M. (Minna), Misiewicz, Z. (Zuzanna), Jukuri, T. (Tuomas), Männynsalo, T. (Teemu), Wegelius, A. (Asko), Haaki, W. (Willehard), Kajanne, R. (Risto), Kyttälä, A. (Aija), Tuulio-Henriksson, A. (Annamari), Lahdensuo, K. (Kaisla), Häkkinen, K. (Katja), Hietala, J. (Jarmo), Paunio, T. (Tiina), Niemi-Pynttäri, J. (Jussi), Kieseppä, T. (Tuula), Veijola, J. (Juha), Lönnqvist, J. (Jouko), Isometsä, E. (Erkki), Kampman, O. (Olli), Tiihonen, J. (Jari), Hyman, S. (Steven), Neale, B. (Benjamin), Daly, M. (Mark), Suvisaari, J. (Jaana), and Palotie, A. (Aarno)

Abstract

Purpose: SUPER-Finland is a large Finnish collection of psychosis cases. This cohort also represents the Finnish contribution to the Stanley Global Neuropsychiatric Genetics Initiative, which seeks to diversify genetic sample collection to include Asian, Latin American and African populations in addition to known population isolates, such as Finland. Participants: 10 474 individuals aged 18 years or older were recruited throughout the country. The subjects have been genotyped with a genome-wide genotyping chip and exome sequenced. A subset of 897 individuals selected from known population sub-isolates were selected for whole-genome sequencing. Recruitment was done between November 2015 and December 2018. Findings to date: 5757 (55.2%) had a diagnosis of schizophrenia, 944 (9.1%) schizoaffective disorder, 1612 (15.5%) type I or type II bipolar disorder, 532 (5.1 %) psychotic depression, 1047 (10.0%) other psychosis and for 530 (5.1%) self-reported psychosis at recruitment could not be confirmed from register data. Mean duration of schizophrenia was 22.0 years at the time of the recruitment. By the end of the year 2018, 204 of the recruited individuals had died. The most common cause of death was cardiovascular disease (n=61) followed by neoplasms (n=40). Ten subjects had psychiatric morbidity as the primary cause of death. Future plans: Compare the effects of common variants, rare variants and copy number variations (CNVs) on severity of psychotic illness. In addition, we aim to track longitudinal course of illness based on nation-wide register data to estimate how phenotypic and genetic differences alter it.

Published
2023

2. A novel variant in SMG9 causes intellectual disability, confirming a role for nonsense-mediated decay components in neurocognitive development

Author

Rahikkala, E. (Elisa), Urpa, L. (Lea), Ghimire, B. (Bishwa), Topa, H. (Hande), Kurki, M. I. (Mitja I.), Koskela, M. (Maryna), Airavaara, M. (Mikko), Hämäläinen, E. (Eija), Pylkäs, K. (Katri), Körkkö, J. (Jarmo), Savolainen, H. (Helena), Suoranta, A. (Anu), Bertoli-Avella, A. (Aida), Rolfs, A. (Arndt), Mattila, P. (Pirkko), Daly, M. (Mark), Palotie, A. (Aarno), Pietiläinen, O. (Olli), Moilanen, J. (Jukka), Kuismin, O. (Outi), Rahikkala, E. (Elisa), Urpa, L. (Lea), Ghimire, B. (Bishwa), Topa, H. (Hande), Kurki, M. I. (Mitja I.), Koskela, M. (Maryna), Airavaara, M. (Mikko), Hämäläinen, E. (Eija), Pylkäs, K. (Katri), Körkkö, J. (Jarmo), Savolainen, H. (Helena), Suoranta, A. (Anu), Bertoli-Avella, A. (Aida), Rolfs, A. (Arndt), Mattila, P. (Pirkko), Daly, M. (Mark), Palotie, A. (Aarno), Pietiläinen, O. (Olli), Moilanen, J. (Jukka), and Kuismin, O. (Outi)

Abstract

Biallelic loss-of-function variants in the SMG9 gene, encoding a regulatory subunit of the mRNA nonsense-mediated decay (NMD) machinery, are reported to cause heart and brain malformation syndrome. Here we report five patients from three unrelated families with intellectual disability (ID) and a novel pathogenic SMG9 c.551 T > C p.(Val184Ala) homozygous missense variant, identified using exome sequencing. Sanger sequencing confirmed recessive segregation in each family. SMG9 c.551T > C p.(Val184Ala) is most likely an autozygous variant identical by descent. Characteristic clinical findings in patients were mild to moderate ID, intention tremor, pyramidal signs, dyspraxia, and ocular manifestations. We used RNA sequencing of patients and age- and sex-matched healthy controls to assess the effect of the variant. RNA sequencing revealed that the SMG9 c.551T > C variant did not affect the splicing or expression level of SMG9 gene products, and allele-specific expression analysis did not provide evidence that the nonsense mRNA-induced NMD was affected. Differential gene expression analysis identified prevalent upregulation of genes in patients, including the genes SMOX, OSBP2, GPX3, and ZNF155. These findings suggest that normal SMG9 function may be involved in transcriptional regulation without affecting nonsense mRNA-induced NMD. In conclusion, we demonstrate that the SMG9 c.551T > C missense variant causes a neurodevelopmental disorder and impacts gene expression. NMD components have roles beyond aberrant mRNA degradation that are crucial for neurocognitive development.

Published
2022

3. Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

Author

Häkkinen, K. (Katja), Kiiski, J. I. (Johanna I.), Lähteenvuo, M. (Markku), Jukuri, T. (Tuomas), Suokas, K. (Kimmo), Niemi-Pynttäri, J. (Jussi), Kieseppä, T. (Tuula), Männynsalo, T. (Teemu), Wegelius, A. (Asko), Haaki, W. (Willehard), Lahdensuo, K. (Kaisla), Kajanne, R. (Risto), Kaunisto, M. A. (Mari A.), Tuulio-Henriksson, A. (Annamari), Kampman, O. (Olli), Hietala, J. (Jarmo), Veijola, J. (Juha), Lönnqvist, J. (Jouko), Isometsä, E. (Erkki), Paunio, T. (Tiina), Suvisaari, J. (Jaana), Kalso, E. (Eija), Niemi, M. (Mikko), Tiihonen, J. (Jari), Daly, M. (Mark), Palotie, A. (Aarno), Ahola-Olli, A. V. (Ari V.), Häkkinen, K. (Katja), Kiiski, J. I. (Johanna I.), Lähteenvuo, M. (Markku), Jukuri, T. (Tuomas), Suokas, K. (Kimmo), Niemi-Pynttäri, J. (Jussi), Kieseppä, T. (Tuula), Männynsalo, T. (Teemu), Wegelius, A. (Asko), Haaki, W. (Willehard), Lahdensuo, K. (Kaisla), Kajanne, R. (Risto), Kaunisto, M. A. (Mari A.), Tuulio-Henriksson, A. (Annamari), Kampman, O. (Olli), Hietala, J. (Jarmo), Veijola, J. (Juha), Lönnqvist, J. (Jouko), Isometsä, E. (Erkki), Paunio, T. (Tiina), Suvisaari, J. (Jaana), Kalso, E. (Eija), Niemi, M. (Mikko), Tiihonen, J. (Jari), Daly, M. (Mark), Palotie, A. (Aarno), and Ahola-Olli, A. V. (Ari V.)

Abstract

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.

Published
2022

4. Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Author

Natarajan, P. (Pradeep), Pampana, A. (Akhil), Graham, S. E. (Sarah E.), Ruotsalainen, S. E. (Sanni E.), Perry, J. A. (James A.), de Vries, P. S. (Paul S.), Broome, J. G. (Jai G.), Pirruccello, J. P. (James P.), Honigbere, M. C. (Michael C.), Aragam, K. (Krishna), Wolford, B. (Brooke), Brody, J. A. (Jennifer A.), Antonacci-Fulton, L. (Lucinda), Arden, M. (Moscati), Aslibekyan, S. (Stella), Assimes, T. L. (Themistocles L.), Ballantyne, C. M. (Christie M.), Bielak, L. F. (Lawrence F.), Bisl, J. C. (Joshua C.), Cade, B. E. (Brian E.), Do, R. (Ron), Doddapaneni, H. (Harsha), Emery, L. S. (Leslie S.), Hung, Y.-J. (Yi-Jen), Irvin, M. R. (Marguerite R.), Khan, A. T. (Alyna T.), Lange, L. (Leslie), Lee, J. (Jiwon), Lemaitre, R. N. (Rozenn N.), Martin, L. W. (Lisa W.), Metcalf, G. (Ginger), Montasser, M. E. (May E.), Moon, J.-Y. (Jee-Young), Muzny, D. (Donna), Connell, J. R. (Jeffrey R. O.), Palmer, N. D. (Nicholette D.), Peralta, J. M. (Juan M.), Peyser, P. A. (Patricia A.), Stilp, A. M. (Adrienne M.), Tsai, M. (Michael), Wang, F. F. (Fei Fei), Weeks, D. E. (Daniel E.), Yanek, L. R. (Lisa R.), Wilson, J. G. (James G.), Abecasis, G. (Goncalo), Arnett, D. K. (Donna K.), Becker, L. C. (Lewis C.), Blangercy, J. (John), Boerwinkle, E. (Eric), Bowden, D. W. (Donald W.), Chang, Y.-C. (Yi-Cheng), Chen, Y. I. (Yii-Der, I), Choi, W. J. (Won Jung), Correa, A. (Adolfo), Curran, J. E. (Joanne E.), Daly, M. J. (Mark J.), DutcherE, S. K. (Susan K.), Ellinor, P. T. (Patrick T.), Fornage, M. (Myriam), Freedman, B. I. (Barry, I), Gabriel, S. (Stacey), Germer, S. (Soren), Gibbs, R. A. (Richard A.), He, J. (Jiang), Hveem, K. (Kristian), Jarvik, G. P. (Gail P.), Kaplan, R. C. (Robert C.), Kardia, S. L. (Sharon L. R.), Kennyn, E. (Eimear), Kim, R. W. (Ryan W.), Kooperberg, C. (Charles), Laurie, C. C. (Cathy C.), Lee, S. (Seonwook), Lloyd-Jones, D. M. (Don M.), Loos, R. J. (Ruth J. F.), Lubitz, S. A. (Steven A.), Mathias, R. A. (Rasika A.), Martinez, K. A. (Karine A. Viaud), McGarvey, S. T. (Stephen T.), Mitche, B. D. (Braxton D.), Nickerson, D. A. (Deborah A.), North, K. E. (Kari E.), Palotie, A. (Aarno), Park, C. J. (Cheol Joo), Psat, B. M. (Bruce M. Y.), Rao, D. C. (D. C.), Redline, S. (Susan), Reiner, A. P. (Alexander P.), Seo, D. (Daekwan), Seo, J.-S. (Jeong-Sun), Smith, A. V. (Albert, V), Tracy, R. P. (Russell P.), Kathiresan, S. (Sekar), Cupples, L. A. (L. Adrienne), Rotten, J. I. (Jerome, I), Morrison, A. C. (Alanna C.), Rich, S. S. (Stephen S.), Ripatti, S. (Samuli), Wilier, C. (Cristen), Peloso, G. M. (Gina M.), Vasan, R. S. (Ramachandran S.), Abe, N. (Namiko), Albert, C. (Christine), Almasy, L. (Laura), Alonso, A. (Alvaro), Ament, S. (Seth), Anderson, P. (Peter), Applebaum-Bowden, D. (Deborah), Arking, D. (Dan), Ashley-Koch, A. (Allison), Auer, P. (Paul), Avramopoulos, D. (Dimitrios), Barnard, J. (John), Barnes, K. (Kathleen), Barr, R. G. (R. Graham), Barron-Casella, E. (Emily), Beaty, T. (Terri), Becker, D. (Diane), Beer, R. (Rebecca), Begum, F. (Ferdouse), Beitelshees, A. (Amber), Benjamin, E. (Emelia), Bezerra, M. (Marcos), Bielak, L. (Larry), Blackwel, T. (Thomas), Bowler, R. (Russell), Broecke, U. (Ulrich), Bunting, K. (Karen), Burchard, E. (Esteban), Buth, E. (Erin), Cardwel, J. (Jonathan), Carty, C. (Cara), Casaburi, R. (Richard), Casella, J. (James), Chaffin, M. (Mark), Chang, C. (Christy), Chasman, D. (Daniel), Chavan, S. (Sameer), Chen, B.-J. (Bo-Juen), Chen, W.-M. (Wei-Min), Chol, M. (Michael), Choi, S. H. (Seung Hoan), Chuang, L.-M. (Lee-Ming), Chung, M. (Mina), Conomos, M. P. (Matthew P.), Cornell, E. (Elaine), Crapo, J. (James), Curtis, J. (Jeffrey), Custer, B. (Brian), Damcott, C. (Coleen), Darbar, D. (Dawood), Das, S. (Sayantan), David, S. (Sean), Davis, C. (Colleen), Daya, M. (Michelle), de Andrade, M. (Mariza), DeBaunuo, M. (Michael), Duan, Q. (Qing), Devine, R. D. (Ranjan Deka Dawn DeMeo Scott), Duggirala, Q. R. (Qing Ravi), Durda, J. P. (Jon Peter), Dutcher, S. (Susan), Eaton, C. (Charles), Ekunwe, L. (Lynette), Farber, C. (Charles), Farnaml, L. (Leanna), Fingerlin, T. (Tasha), Flickinger, M. (Matthew), Franceschini, N. (Nora), Fu, M. (Mao), Fullerton, S. M. (Stephanie M.), Fulton, L. (Lucinda), Gan, W. (Weiniu), Gao, Y. (Yan), Gass, M. (Margery), Ge, B. (Bruce), Geng, X. P. (Xiaoqi Priscilla), Gignoux, C. (Chris), Gladwin, M. (Mark), Glahn, D. (David), Gogarten, S. (Stephanie), Gong, D.-W. (Da-Wei), Goring, H. (Harald), Gu, C. C. (C. Charles), Guan, Y. (Yue), Guo, X. (Xiuqing), Haessler, J. (Jeff), Hall, M. (Michael), Harris, D. (Daniel), Hawle, N. Y. (Nicola Y.), Heavner, B. (Ben), Heckbert, S. (Susan), Hernandez, R. (Ryan), Herrington, D. (David), Hersh, C. (Craig), Hidalgo, B. (Bertha), Hixson, J. (James), Hokanson, J. (John), Hong, E. (Elliott), Hoth, K. (Karin), Hsiung, C. A. (Chao Agnes), Huston, H. (Haley), Hwu, C. M. (Chii Min), Jackson, R. (Rebecca), Jain, D. (Deepti), Jaquish, C. (Cashell), Jhun, M. A. (Min A.), Johnsen, J. (Jill), Johnson, A. (Andrew), Johnson, C. (Craig), Johnston, R. (Rich), Jones, K. (Kimberly), Kang, H. M. (Hyun Min), Kaufman, L. (Laura), Kell, S. Y. (Shannon Y.), Kessler, M. (Michael), Kinney, G. (Greg), Konkle, B. (Barbara), Kramer, H. (Holly), Krauter, S. (Stephanie), Lange, C. (Christoph), Lange, E. (Ethan), Laurie, C. (Cecelia), LeBoff, M. (Meryl), Lee, S. S. (Seunggeun Shawn), Lee, W.-J. (Wen-Jane), LeFaive, J. (Jonathon), Levine, D. (David), Levy, D. (Dan), Lewis, J. (Joshua), Li, Y. (Yun), Lin, H. (Honghuang), Lin, K. H. (Keng Han), Lin, X. (Xihong), Liu, S. (Simin), Liu, Y. (Yongmei), Lunetta, K. (Kathryn), Luo, J. (James), Mahaney, M. (Michael), Make, B. (Barry), Manichaikul, A. (Ani), Mansonl, J. (JoAnn), Margolin, L. (Lauren), Mathai, S. (Susan), McArdle, P. (Patrick), Mcdonald, M.-L. (Merry-Lynn), McFarland, S. (Sean), McHugh, C. (Caitlin), Mei, H. (Hao), Meyers, D. A. (Deborah A.), Mikulla, J. (Julie), Min, N. (Nancy), Minear, M. (Mollie), Minster, R. L. (Ryan L.), Musani, S. (Solomon), Mwasongwe, S. (Stanford), Mychaleckyj, J. C. (Josyf C.), Nadkarni, G. (Girish), Naik, R. (Rakhi), Naseri, T. (Take), Nekhai, S. (Sergei), Nelson, S. C. (Sarah C.), Nickerson, D. (Deborah), Connell, J. O. (Jeff O.), Connor, T. O. (Tim O.), Ochs-Balcom, H. (Heather), Pankow, J. (James), Papanicolaou, G. (George), Parkerl, M. (Margaret), Parsa, A. (Afshin), Penchey, S. (Sara), Perez, M. (Marco), Peters, U. (Ulrike), Phillips, L. S. (Lawrence S.), Phillips, S. (Sam), Pollin, T. (Toni), Post, W. (Wendy), Becker, J. P. (Julia Powers), Boorgula, M. P. (Meher Preethi), Preuss, M. (Michael), Prokopenko, D. (Dmitry), Qasba, P. (Pankaj), Qiao, D. (Dandi), Rafaels, N. (Nicholas), Raffield, L. (Laura), Rasmussen-Torvik, L. (Laura), Ratan, A. (Aakrosh), Reed, R. (Robert), Reganl, E. (Elizabeth), Reupena, M. S. (Muagututi Sefuiva), Rice, K. (Ken), Roden, D. (Dan), Roselli, C. (Carolina), Ruczinski, I. (Ingo), Russel, P. (Pamela), Ruuska, S. (Sarah), Ryan, K. (Kathleen), Sabino, E. C. (Ester Cerdeira), Sakornsakolpatl, P. (Phuwanat), Salzberg, S. (Steven), Sandow, K. (Kevin), Sankaran, V. G. (Vijay G.), Scheller, C. (Christopher), Schmidt, E. (Ellen), Schwander, K. (Karen), Schwartz, D. (David), Sciurba, F. (Frank), Seidman, C. (Christine), Seidman, J. (Jonathan), Sheehan, V. (Vivien), Shetty, A. (Amol), Shetty, A. (Aniket), Sheu, W. H. (Wayne Hui-Heng), Shoemaker, M. B. (M. Benjamin), Silver, B. (Brian), Silvermanl, E. (Edwin), Smith, J. (Jennifer), Smith, J. (Josh), Smith, N. (Nicholas), Smith, T. (Tanja), Smoller, S. (Sylvia), Snively, B. (Beverly), Soferlm, T. (Tamar), Streeten, E. (Elizabeth), Su, J. L. (Jessica Lasky), Sung, Y. J. (Yun Ju), Sylvia, J. (Jody), Sztalryd, C. (Carole), Taliun, D. (Daniel), Tang, H. (Hua), Taub, M. (Margaret), Taylor, K. D. (Kent D.), Taylor, S. (Simeon), Telen, M. (Marilyn), Thornton, T. A. (Timothy A.), Tinker, L. (Lesley), Tirschwel, D. (David), Tiwari, H. (Hemant), Vaidya, D. (Dhananjay), VandeHaar, P. (Peter), Vrieze, S. (Scott), Walker, T. (Tarik), Wallace, R. (Robert), Waits, A. (Avram), Wan, E. (Emily), Wang, H. (Heming), Watson, K. (Karol), Weir, B. (Bruce), Weiss, S. (Scott), Weng, L.-C. (Lu-Chen), Williams, K. (Kayleen), Williams, L. K. (L. Keoki), Wilson, C. (Carla), Wong, Q. (Quenna), Xu, H. (Huichun), Yang, I. (Ivana), Yang, R. (Rongze), Zaghlou, N. (Norann), Zekavat, M. (Maryam), Zhang, Y. (Yingze), Zhao, S. X. (Snow Xueyan), Zhao, W. (Wei), Zni, D. (Degui), Zhou, X. (Xiang), Zhu, X. (Xiaofeng), Zody, M. (Michael), Zoellner, S. (Sebastian), Daly, M. (Mark), Jacob, H. (Howard), Matakidou, A. (Athena), Runz, H. (Heiko), John, S. (Sally), Plenge, R. (Robert), McCarthy, M. (Mark), Hunkapiller, J. (Julie), Ehm, M. (Meg), Waterworth, D. (Dawn), Fox, C. (Caroline), Malarstig, A. (Anders), Klinger, K. (Kathy), Call, K. (Kathy), Mkel, T. (Tomi), Kaprio, J. (Jaakko), Virolainen, P. (Petri), Pulkki, K. (Kari), Kilpi, T. (Terhi), Perola, M. (Markus), Partanen, J. (Jukka), Pitkranta, A. (Anne), Kaarteenaho, R. (Riitta), Vainio, S. (Seppo), Savinainen, K. (Kimmo), Kosma, V.-M. (Veli-Matti), Kujala, U. (Urho), Tuovila, O. (Outi), Hendolin, M. (Minna), Pakkanen, R. (Raimo), Waring, J. (Jeff), Riley-Gillis, B. (Bridget), Liu, J. (Jimmy), Biswas, S. (Shameek), Diogo, D. (Dorothee), Marshall, C. (Catherine), Hu, X. (Xinli), Gossel, M. (Matthias), Schleutker, J. (Johanna), Arvas, M. (Mikko), Hinttala, R. (Reetta), Kettunen, J. (Johannes), Laaksonen, R. (Reijo), Mannermaa, A. (Arto), Paloneva, J. (Juha), Soininen, H. (Hilkka), Julkunen, V. (Valtteri), Remes, A. (Anne), Klviinen, R. (Reetta), Hiltunen, M. (Mikko), Peltola, J. (Jukka), Tienari, P. (Pentti), Rinne, J. (Juha), Ziemann, A. (Adam), Waring, J. (Jeffrey), Esmaeeli, S. (Sahar), Smaoui, N. (Nizar), Lehtonen, A. (Anne), Eaton, S. (Susan), Landenper, S. (Sanni), Michon, J. (John), Kerchner, G. (Geoff), Bowers, N. (Natalie), Teng, E. (Edmond), Eicher, J. (John), Mehta, V. (Vinay), Gormle, P. Y. (Padhraig Y.), Linden, K. (Kari), Whelan, C. (Christopher), Xu, F. (Fanli), Pulford, D. (David), Frkkil, M. (Martti), Pikkarainen, S. (Sampsa), Jussila, A. (Airi), Blomster, T. (Timo), Kiviniemi, M. (Mikko), Voutilainen, M. (Markku), Georgantas, B. (Bob), Heap, G. (Graham), Rahimov, F. (Fedik), Usiskin, K. (Keith), Maranville, J. (Joseph), Lu, T. (Tim), Oh, D. (Danny), Kalpala, K. (Kirsi), Miller, M. (Melissa), McCarthy, L. (Linda), Eklund, K. (Kari), Palomki, A. (Antti), Isomki, P. (Pia), Piri, L. (Laura), Kaipiainen-Seppnen, O. (Oili), Lertratanaku, A. (Apinya), Bing, D. C. (David Close Marla Hochfeld Nan), Gordillo, J. E. (Jorge Esparza), Mars, N. (Nina), Laitinen, T. (Tarja), Pelkonen, M. (Margit), Kauppi, P. (Paula), Kankaanranta, H. (Hannu), Harju, T. (Terttu), Greenberg, S. (Steven), Chen, H. (Hubert), Betts, J. (Jo), Ghosh, S. (Soumitra), Salomaa, V. (Veikko), Niiranen, T. (Teemu), Juonala, M. (Markus), Metsrinne, K. (Kaj), Khnen, M. (Mika), Junttila, J. (Juhani), Laakso, M. (Markku), Pihlajamki, J. (Jussi), Sinisalo, J. (Juha), Taskinen, M.-R. (Marja-Riitta), Tuomi, T. (Tiinamaija), Laukkanen, J. (Jari), Challis, B. (Ben), Peterson, A. (Andrew), Chu, A. (Audrey), Parkkinen, J. (Jaakko), Muslin, A. (Anthony), Joensuu, H. (Heikki), Meretoja, T. (Tuomo), Aaltonen, L. (Lauri), Auranen, A. (Annika), Karihtala, P. (Peeter), Kauppila, S. (Saila), Auvinen, P. (Pivi), Elenius, K. (Klaus), Popovic, R. (Relja), Schutzman, J. (Jennifer), Loboda, A. (Andrey), Chhibber, A. (Aparna), Lehtonen, H. (Heli), McDonough, S. (Stefan), Crohns, M. (Marika), Kulkarni, D. (Diptee), Kaarniranta, K. (Kai), Turunen, J. (Joni), Ollila, T. (Terhi), Seitsonen, S. (Sanna), Uusitalo, H. (Hannu), Aaltonen, V. (Vesa), Uusitalo-Jrvinen, H. (Hannele), Luodonp, M. (Marja), Hautala, N. (Nina), Strauss, E. (Erich), Chen, H. (Hao), Podgornaia, A. (Anna), Hoffman, J. (Joshua), Tasanen, K. (Kaisa), Huilaja, L. (Laura), Hannula-Jouppi, K. (Katariina), Salmi, T. (Teea), Peltonen, S. (Sirkku), Koulu, L. (Leena), Harvima, I. (Ilkka), Wu, Y. (Ying), Choy, D. (David), Jalanko, A. (Anu), Kajanne, R. (Risto), Lyhs, U. (Ulrike), Kaunisto, M. (Mari), Davis, J. W. (Justin Wade), Quarless, D. (Danjuma), Petrovski, S. (Slav), Chen, C.-Y. (Chia-Yen), Bronson, P. (Paola), Yang, R. (Robert), Chang, D. (Diana), Bhangale, T. (Tushar), Holzinger, E. (Emily), Wang, X. (Xulong), Chen, X. (Xing), Auro, K. (Kirsi), Wang, C. (Clarence), Xu, E. (Ethan), Auge, F. (Franck), Chatelain, C. (Clement), Kurki, M. (Mitja), Karjalainen, J. (Juha), Havulinna, A. (Aki), Palin, K. (Kimmo), Palta, P. (Priit), Parolo, P. D. (Pietro Della Briotta), Zhou, W. (Wei), Lemmel, S. (Susanna), Rivas, M. (Manuel), Harju, J. (Jarmo), Lehisto, A. (Arto), Ganna, A. (Andrea), Llorens, V. (Vincent), Karlsson, A. (Antti), Kristiansson, K. (Kati), Hyvrinen, K. (Kati), Ritari, J. (Jarmo), Wahlfors, T. (Tiina), Koskinen, M. (Miika), Pylkäs, K. (Katri), Kalaoja, M. (Marita), Karjalainen, M. (Minna), Mantere, T. (Tuomo), Kangasniemi, E. (Eeva), Heikkinen, S. (Sami), Laakkonen, E. (Eija), Kononen, J. (Juha), Loukola, A. (Anu), Laiho, P. (Pivi), Sistonen, T. (Tuuli), Kaiharju, E. (Essi), Laukkanen, M. (Markku), Jrvensivu, E. (Elina), Lhteenmki, S. (Sini), Mnnikk, L. (Lotta), Wong, R. (Regis), Mattsson, H. (Hannele), Hiekkalinna, T. (Tero), Jimnez, M. G. (Manuel Gonzlez), Donner, K. (Kati), Prn, K. (KaIle), Nunez-Fontarnau, J. (Javier), Kilpelinen, E. (Elina), Sipi, T. P. (Timo P.), Brein, G. (Georg), Dada, A. (Alexander), Awaisa, G. (Ghazal), Shcherban, A. (Anastasia), Sipil, T. (Tuomas), Laivuori, H. (Hannele), Kiiskinen, T. (Tuomo), Siirtola, H. (Harri), Tabuenca, J. G. (Javier Gracia), Kallio, L. (Lila), Soini, S. (Sirpa), Pitknen, K. (Kimmo), and Kuopio, T. (Teijo)

Subjects
Cardiovascular genetics, Genome-wide association studies
Abstract

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Published
2021

5. Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants

Author

Saarentaus, E. C. (Elmo Christian), Havulinna, A. S. (Aki Samuli), Mars, N. (Nina), Ahola-Olli, A. (Ari), Kiiskinen, T. T. (Tuomo Tapio Johannes), Partanen, J. (Juulia), Ruotsalainen, S. (Sanni), Kurki, M. (Mitja), Urpa, L. M. (Lea Martta), Chen, L. (Lei), Perola, M. (Markus), Salomaa, V. (Veikko), Veijola, J. (Juha), Männikkö, M. (Minna), Hall, I. M. (Ira M.), Pietiläinen, O. (Olli), Kaprio, J. (Jaakko), Ripatti, S. (Samuli), Daly, M. (Mark), Palotie, A. (Aarno), Saarentaus, E. C. (Elmo Christian), Havulinna, A. S. (Aki Samuli), Mars, N. (Nina), Ahola-Olli, A. (Ari), Kiiskinen, T. T. (Tuomo Tapio Johannes), Partanen, J. (Juulia), Ruotsalainen, S. (Sanni), Kurki, M. (Mitja), Urpa, L. M. (Lea Martta), Chen, L. (Lei), Perola, M. (Markus), Salomaa, V. (Veikko), Veijola, J. (Juha), Männikkö, M. (Minna), Hall, I. M. (Ira M.), Pietiläinen, O. (Olli), Kaprio, J. (Jaakko), Ripatti, S. (Samuli), Daly, M. (Mark), and Palotie, A. (Aarno)

Abstract

Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66–0.89]) and lower household income (OR = 0.77 [0.66–0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38–0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32–0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26–0.37]), lower-income (OR = 0.66 [0.57–0.77]), lower subjective health (OR = 0.72 [0.61–0.83]), and increased mortality (Cox’s HR = 1.55 [1.21–1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of trad

Published
2021

6. The role of polygenic risk and susceptibility genes in breast cancer over the course of life

Author

Mars, N. (Nina), Widén, E. (Elisabeth), Kerminen, S. (Sini), Meretoja, T. (Tuomo), Pirinen, M. (Matti), della Briotta Parolo, P. (Pietro), Palta, P. (Priit), . (), Palotie, A. (Aarno), Kaprio, J. (Jaakko), Joensuu, H. (Heikki), Daly, M. (Mark), Ripatti, S. (Samuli), Mars, N. (Nina), Widén, E. (Elisabeth), Kerminen, S. (Sini), Meretoja, T. (Tuomo), Pirinen, M. (Matti), della Briotta Parolo, P. (Pietro), Palta, P. (Priit), . (), Palotie, A. (Aarno), Kaprio, J. (Jaakko), Joensuu, H. (Heikki), Daly, M. (Mark), and Ripatti, S. (Samuli)

Abstract

Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer, and that the PRS can considerably improve risk assessment among their female first-degree relatives. In more detail, women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 336 carriers) and an average PRS (10–90th percentile) have a lifetime risk of breast cancer at 55% (95% CI 49–61%), which increases to 84% (71–97%) with a high PRS ( > 90th percentile), and decreases to 49% (30–68%) with a low PRS ( < 10th percentile). Similarly, for c.1100delC in CHEK2 (3.7–fold enrichment; 1648 carriers), the respective lifetime risks are 29% (27–32%), 59% (52–66%), and 9% (5–14%). The PRS also refines the risk assessment of women with first-degree relatives diagnosed with breast cancer, particularly among women with positive family history of early-onset breast cancer. Here we demonstrate the opportunities for a comprehensive way of assessing genetic risk in the general population, in breast cancer patients, and in unaffected family members., FinnGen Aarno Palotie1,7,8, Aki Havulinna1, Amanda Elliott1,8, Anastasia Shcherban1, Andrea Ganna1, Anu Jalanko1, Arto Lehisto1, Elina Kilpeläinen1, Georg Brein1, Ghazal Awaisa1, Hannele Laivuori1, Henrike Heyne1, Jaakko Kaprio1,5, Jarmo Harju1, Jiwoo Lee1,8, Juha Karjalainen1,8, Jukka Koskela1, Kalle Pärn1, Kati Donner1, Kristin Tsuo1,8, Manuel González Jiménez1, Mark Daly1,8, Mari Kaunisto1, Mari E. Niemi1, Mary Pat Reeve1, Mervi Aavikko1, Mitja Kurki1,8, Nina Mars1, Oluwaseun A. Dada1, Pietro della Briotta Parolo1, Priit Palta1,6, Risto Kajanne1, Samuli Ripatti1,6,8, Sina Rüeger1, Susanna Lemmelä1, Taru Tukiainen1, Tiinamaija Tuomi1, Timo P. Sipilä1, Tuomo Kiiskinen1, Vincent Llorens1, Adam Ziemann10, Anne Lehtonen10, Apinya Lertratanakul10, Bob Georgantas10, Bridget Riley-Gillis10, Danjuma Quarless10, Fedik Rahimov10, Howard Jacob10, Jeffrey Waring10, Justin Wade Davis10, Nizar Smaoui10, Relja Popovic10, Sahar Esmaeeli10, Athena Matakidou11, Ben Challis11, David Close11, Eleonor Wigmore11, Slavé Petrovski11, Chia-Yen Chen12, Ellen Tsai12, Heiko Runz12, Jimmy Liu12, Paola Bronson12, Sally John12, Sanni Lahdenperä12, Stephanie Loomis12, Susan Eaton12, Yunfeng Huang12, Erika Kvikstad13, Minal Caliskan13, Samir Wadhawan13, Elmutaz Shaikho Elhaj Mohammed14, Janet van Adelsberg14, Joseph Maranville14, Marla Hochfeld14, Robert Plenge14, Shameek Biswas14, Steven Greenberg14, Andrew Peterson15, David Choy15, Diana Chang15, Edmond Teng15, Erich Strauss15, Geoff Kerchner15, Hao Chen15, Hubert Chen15, Jennifer Schutzman15, John Michon15, Julie Hunkapiller15, Mark McCarthy15, Natalie Bowers15, Sarah Pendergrass15, Tushar Bhangale15, David Pulford16, Dawn Waterworth16, Diptee Kulkarni16, Fanli Xu16, Jo Betts16, Jorge Esparza Gordillo16, Joshua Hoffman16, Karen S. King16, Meg Ehm16, Soumitra Ghosh16, Patrick Loerch17, Wilco Fleuren17, Beryl Cummings18, Matt Brauer18, Robert Graham18, Tim Behrens18, Andrey Loboda19, Anna Podgornaia19, Aparna Chhibber19, Audrey Chu19, Caroline F

Published
2020

7. Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

Author

Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, L.M.A., Cruchaga, C. (Carlos), Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard A.), Goate, A.M. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Pericak-Vance, M.A. (Margaret), Perola, M. (Markus), Psaty, B.M. (Bruce M.), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Vardarajan, B.N. (Badri), Wang, W. (Weixin), Wijsman, E.M. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M. (Mark), Boerwinkle, E. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Dupuis, J. (Josée), Martin, E.R. (Eden R.), Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), Farrer, L.A. (Lindsay), Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, L.M.A., Cruchaga, C. (Carlos), Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard A.), Goate, A.M. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Pericak-Vance, M.A. (Margaret), Perola, M. (Markus), Psaty, B.M. (Bruce M.), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Vardarajan, B.N. (Badri), Wang, W. (Weixin), Wijsman, E.M. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M. (Mark), Boerwinkle, E. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Dupuis, J. (Josée), Martin, E.R. (Eden R.), Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), and Farrer, L.A. (Lindsay)

Abstract

The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 contro

Published
2018
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