An association between advanced paternal age at birth and risk for autism spectrum disorders and the underlying biological mechanisms

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591396
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: TSUCHIYA Kenji Hamamatsu University School of Medicine, 子どものこころの発達研究センター, 特任准教授 (20362189)
• Co-Investigator(Kenkyū-buntansha): MATSUMOTO Kaori 浜松医科大学, 子どものこころの発達研究センター, 特任助教 ; KANAYAMA Naohiro 浜松医科大学, 医学部・産婦人科医学講座, 教授 ; SUZUKI Katsuaki 浜松医科大学, 子どものこころの発達研究センター, 特任准教授 ; NAKAMURA Kazuhiko 浜松医科大学, 医学部・精神医学講座, 准教授 ; MATSUZAKI Hideo 浜松医科大学, 子どものこころの発達研究センター, 特任准教授 ; TSUJII Masatsugu 中京大学, 現代社会学部, 教授 ; TAKEI Noriyoshi 浜松医科大学, 子どものこころの発達研究センター, 教授
• Co-Investigator(Renkei-kenkyūsha): ITOH Hiroaki 浜松医科大学, 医学部・周産母子センター, 臨床教授
• Project Period (FY): 2008 – 2010
• Keywords: 自閉症スペクトラム / 言語 / 生殖補助医療 / 疫学 / コホート研究

Research Abstract

Background and aim. Paternal age at birth has been suggested to be associated with autism spectrum disorder (ASD). In this study, we aimed at replicating the association in a Japanese sample in a retrospective manner, and at investigating biological mechanisms underlying this association using a birth cohort. A potential candidate for this mechanism is a use of artificial reproductive technique.
Method 1. "Retrospective study" : 84 individuals with high-functioning ASD and 208 typically developed control individuals were enrolled. A statistical association was sought between diagnosis of ASD and paternal age at birth, while controlling for gender, parity, and maternal age at birth.
Method 2. "Prospective study" : 780 pregnant women and their babies were enrolled as a part of an ongoing birth cohort study who were born during the period of 19 November, 2007 and 1 July, 2009. The participating mother-and-child dyads were followed up until the end of 2010 to examine whether any aberrant dev elopmental trajectories would be found ; such outcome measures include scores of Mullen Scales of Early Learning, developmental milestones, and suspected diagnosis of ASD. We also examined a risk of suspected ASD in association with paternal age at birth, and artificial reproductive technique as well. Result 1. "Retrospective study" : The association between paternal age at birth and a risk for ASD was confirmed after controlling for covariates. The dose-response relationship was also found.
Result 2. "Prospective study" : In univariate analyses, paternal age at birth did not predict delay in motor/language development, in achievement of developmental milestones, and suspected diagnosis of ASD. On the other hand, artificial reproductive technique appeared to predict delayed development and ASD, although the associations did not reach statistical significance. Due to lack of statistical power, we were unable to seek for interaction between paternal age at birth and artificial reproductive therapy in association with a risk for ASD.
Conclusion. Although firm conclusions are awaited, this study suggested relevance of artificial reproductive techniques as an underlying biological mechanism for the association between paternal age at birth and ASD.

Research Products

• [Journal Article] Jiko-shisen-kyofu (fear of one's own glance), but not taijin-kyofusho (fear of interpersonal relations), is an east Asian culture-related specific syndrome. (2011)
  • Author(s): Iwata Y, Suzuki K, Takei N, Toulopoulou T, Tsuchiya KJ, Matsumoto K, Takagai S, Oshiro M, Nakamura K, Mori N.
  • Journal Title: Australian and New Zealand Journal of Psychiatry 45 Pages: 148-152
• [Journal Article] Reduced acetylcholinesterase activity in the fusiform gyrus in adults with autism spectrum disorders. (2011)
  • Author(s): Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Tsujii M, Futatsubashi M, Iwata Y, Tsuchiya KJ, Matsumoto K, Takebayashi K, Wakuda T, Yoshihara Y, Suda S, Kikuchi M, Takei N, Sugiyama T, Irie T, Mori N.
  • Journal Title: Archives of General Psychiatry 68 Pages: 306-313
• [Journal Article] Association analyses between brain-expressed fatty-acid binding protein (FABP) genes and schizophrenia and bipolar disorder. (2010)
  • Author(s): Iwayama Y, Hattori E, Maekawa M, Yamada K, Toyota T, Ohnishi T, Iwata Y, Tsuchiya KJ, Sugihara G, Kikuchi M, Hashimoto K, Iyo M, Inada T, Kunugi H, Ozaki N, Iwata N, Nanko S, Iwamoto K, Okazaki Y, Kato T, Yoshikawa T.
  • Journal Title: American Journal of Medical Genetics B Neuropsychiatric Genetics 153B Pages: 484-493
• [Journal Article] Serum levels of platelet-derived growth factor BB homodimers are increased in male children with autism. (2010)
  • Author(s): Kajizuka M, Miyachi T, Matsuzaki H, Iwata K, Shinmura C, Suzuki K, Suda S, Tsuchiya KJ, Matsumoto K, Iwata Y, Nakamura K, Tsujii M, Sugiyama T, Takei N, Mori N.
  • Journal Title: Progress in Neuropsychopharmacology and Biological Psychiatry 34 Pages: 154-158
• [Journal Article] Decreased serum levels of adiponectin in subjects with autism. (2010)
  • Author(s): Fujita-Shimizu A, Suzuki K, Nakamura K, Miyachi T, Matsuzaki H, Kajizuka M, Shinmura C, Iwata Y, Suda S, Tsuchiya KJ, Matsumoto K, Sugihara G, Iwata K, Yamamoto S, Tsujii M, Sugiyama T, Takei N, Mori N.
  • Journal Title: Progress in Neuropsychopharmacology and Biological Psychiatry 34 Pages: 455-458
• [Journal Article] Reduced expression of apolipoprotein E receptor type 2 in peripheral blood lymphocytes from patients with major depressive disorder. (2010)
  • Author(s): Suzuki K, Iwata Y, Matsuzaki H, Anitha A, Suda S, Iwata K, Shinmura C, Kameno Y, Tsuchiya KJ, Nakamura K, Takei N, Mori N.
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry 34 Pages: 1007-1010
• [Journal Article] Brain seronin and dopamine transporter bindings in adults with high-functioning autism. (2010)
  • Author(s): Nakamura K, Sekine Y, Ouchi Y, Tsujii M, Yoshikawa E, Futatsubashi M, Tsuchiya KJ, Sugihara G, Iwata Y, Suzuki K, Matsuzaki H, Suda S, Sugiyama T, Takei N, Mori N.
  • Journal Title: Archives of General Psychiatry 67 Pages: 59-68
• [Journal Article] Searching for very early precursors of autism spectrum disorders : the Hamamatsu Birth Cohort for Mothers and Children (HBC). (2010)
  • Author(s): Tsuchiya KJ, Matsumoto K, Suda S, Miyachi T, Itoh H, Kanayama N, Hirano K, Ohzeki T, Takei N, the HBC Study Team.
  • Journal Title: Journal of Developmental Origins of Health and Disease 1 Pages: 158-173
• [Journal Article] Further evidence for the role of MET in autism susceptibility. (2010)
  • Author(s): Thanseem I, Nakamura K, Miyachi T, Toyota T, Yamada S, Tsujii M, Tsuchiya KJ, Anitha A, Iwayama Y, Yamada K, Hattori E, Matsuzaki H, Matsumoto K, Iwata Y, Suzuki K, Suda S, Kawai M, Sugihara GI, Takebayashi K, Takei N, Ichikawa H, Sugiyama T, Yoshikawa T, Mori N.
  • Journal Title: Neuroscience Research 68 Pages: 137-141
• [Journal Article] Metabolite alterations in the hippocampus of high-functioning adult subjects with autism. (2009)
  • Author(s): Suzuki K, Nishimura K, Sugihara G, Nakamura K, Tsuchiya KJ, Matsumoto K, Takebayashi K, Isoda H, Sakahara H, Sugiyama T, Tsujii M, Takei N, Mori N.
  • Journal Title: International Journal of Neuropsychopharmacology 13 Pages: 529-534
• [Journal Article] Paternal age at birth and high-functioning autism spectrum disorder in the offspring. (2008)
  • Author(s): Tsuchiya KJ, Matsumoto K, Miyachi T, Tsujii M, Nakamura K, Takagai S, Kawai M, Yagi A, Iwaki K, Suda S, Sugihara G, Iwata Y, Matsuzaki H, Sekine Y, Suzuki K, Sugiyama T, Mori N, Takei N.
  • Journal Title: British Journal of Psychiary 193 Pages: 316-321
• [Journal Article] Serum levels of P-selectin in men with high-functioning autism. (2008)
  • Author(s): Iwata Y, Tsuchiya KJ, Mikawa S, Nakamura K, Takai Y, Suda S, Sekine Y, Suzuki K, Kawai M, Sugihara G, Matsuzaki H, Hashimoto K, Tsujii M, Sugiyama T, Takei N, Mori N.
  • Journal Title: British Journal of Psychiary 193 Pages: 338-339
• [Journal Article] Distinguishing broad autism phenotype from schizophrenia-spectrum disorders. (2008)
  • Author(s): Sugihara G, Tsuchiya KJ, Takei N.
  • Journal Title: Journal of Autism and Developmental Disorders 38 Pages: 1998-1999
• [Journal Article] Voxel-based structural magnetic resonance imaging (MRI) study of patients with early onset schizophrenia. (2008)
  • Author(s): Yoshihara Y, Sugihara G, Matsumoto H, Suckling J, Nishimura K, Toyoda T, Isoda H, Tsuchiya KJ, Takebayashi K, Suzuki K, Sakahara H, Nakamura K, Mori N, Takei N.
  • Journal Title: Annals of General Psychiatry 7 Pages: 25
• [Journal Article] Perinatal asphyxia reduces dentate granule cells and exacerbates methamphetamine-induced hyperlocomotion in adulthood. (2008)
  • Author(s): Wakuda T, Matsuzaki H, Suzuki K, Iwata Y, Shinmura C, Suda S, Iwata K, Yamamoto S, Sugihara G, Tsuchiya KJ, Ueki T, Nakamura K, Nakahara D, Takei N, Mori N.
  • Journal Title: PLoS One 3 Pages: e3648
• [Journal Article] In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer's disease.
  • Author(s): Yokokura M, Mori N, Yagi S, Yoshikawa E, Kikuchi M, Yoshihara Y, Wakuda T, Sugihara G, Takebayashi K, Suda S, Iwata Y, Ueki T, Tsuchiya KJ, Suzuki K, Nakamura K, Ouchi Y.
  • Journal Title: European Journal of Nuclear Medicine and Molecular Imaging in press.
• [Journal Article] Replication study of Japanese cohorts supports the role of STX1A in autism susceptibility.
  • Author(s): Nakamura K, Iwata Y, Anitha A, Miyachi T, Toyota T, Yamada S, Tsujii M, Tsuchiya KJ, Iwayama Y, Yamada K, Hattori E, Matsuzaki H, Matsumoto K, Suzuki K, Suda S, Takebayashi K, Takei N, Ichikawa H, Sugiyama T, Yoshikawa T, Mori N.
  • Journal Title: Progress in Neuropsychopharmacology and Biological Psychiatry in press.
• [Journal Article] Age-specific 3-month cumulative incidence of postpartum depression : The Hamamatsu Birth Cohort Study (HBC).
  • Author(s): Matsumoto K, Tsuchiya KJ, Itoh H, Kanayama N, Suda S, Matsuzaki H, Iwata Y, Suzuki K, Nakamura K, Mori N, Takei N.
  • Journal Title: Journal of Affective Disorders in press.
• [Presentation] Postpartum depression and prepregnancy BMI : the HBC Study. (2010)
  • Author(s): Mori T, Tsuchiya KJ, Matsumoto K, Muraki H, Takahashi S, Takabayashi R, Suzuki Y, Sato R, Narumiya M, Takei N, the HBC Study Team.
  • Organizer: Longitudinal and Life Course Studies 1 (suppl 3) : 372
  • Place of Presentation: [conference proceeding]
  • Year and Date: 20100000
• [Presentation] Mother's unintended pregnancy associated with lower ponderal index at 4 months of the infant : the HBC Study. (2010)
  • Author(s): Takahashi S, Tsuchiya KJ, Matsumoto K, Mori T, Takabayashi R, Suzuki Y, Sato R, Narumiya M, Seno Y, Suda S, Matsuzaki H, Suzuki K, Mori N, Takei N, the HBC Study Team.
  • Organizer: Longitudinal and Life Course Studies 1 (suppl 3) : 373
  • Place of Presentation: [conference proceeding]
  • Year and Date: 20100000
• [Presentation] Early-and late-onset postpartum depression and the associated risk factors : the HBC Study. (2010)
  • Author(s): Tsuchiya KJ, Matsumoto K, Takahashi S, Mori T, Takabayashi R, Suzuki Y, Sato R, Narumiya M, Seno Y, Suda S, Matsuzaki H, Suzuki K, Mori N, Takei N, the HBC Study Team.
  • Organizer: Longitudinal and Life Course Studies 1 (suppl 3) : 374
  • Place of Presentation: [conference proceeding]
  • Year and Date: 20100000
• [Presentation] Searching for causes and effects of an increase in LBW children in Japan : The Hamamatsu Birth Cohort for Mothers and Children (HBC). (2009)
  • Author(s): Tsuchiya KJ, Matsumoto K, Miyachi T, Tsujii M, Itoh H, Kanayama N, Hirano K, Ohzeki T, Takei N, the HBC Study Team, the Hamamatsu DOHaD Study Team.
  • Organizer: The 6th World Congress on Developmental Origins of Health and Disease
  • Place of Presentation: Santiago de Chile
  • Year and Date: 20091119-20091122
• [Presentation] Unwanted pregnancy and its detrimental effect on early language development in the offspring : the HBC Study. (2009)
  • Author(s): Matsumoto K, Tsuchiya KJ, Miyachi T, Itoh H, Kanayama N, Takei N, the HBC Study Team.
  • Organizer: The 6th World Congress on Developmental Origins of Health and Disease
  • Place of Presentation: Santiago de Chile
  • Year and Date: 20091119-20091122
• [Presentation] Advanced paternal age associated with an increased risk for autism spectrum disorder. (2008)
  • Author(s): Tsuchiya KJ, Matsumoto K, Takagai S, Kawai M, Nakamura K, Suda S, Tsujii M, Miyachi T, Mori N, Takei N.
  • Organizer: The 18^<th> Congress for International Association for Epidemiology
  • Place of Presentation: Porto Alegre
  • Year and Date: 20080920-20080924
• [Presentation] Validating a Japanese version of the Ritvo Autism and Asperger's Diagnostic Scale : a pilot study. (2008)
  • Author(s): Matsumoto K, Tsuchiya KJ, Ritvo ER, Tsujii M.
  • Organizer: The 8th International Meeting for Autism Research
  • Place of Presentation: London
  • Year and Date: 20080515-20080517
• [Remarks] ホームページ等
  • URL: http://rccmd.org/
• [Patent(Industrial Property Rights)] 自閉症の診断薬 (2011)
  • Inventor(s): 橋本謙二, 伊予雅臣, 森則夫, 武井教使, 三辺義雄, 中村和彦, 岩田泰秀, 関根吉統, 土屋賢治, 辻井正次
  • Industrial Property Rights Holder: 橋本謙二, 伊予雅臣, 森則夫, 武井教使, 三辺義雄, 中村和彦, 岩田泰秀, 関根吉統, 土屋賢治, 辻井正次
  • Industrial Property Number: 特許,第4677556号
  • Acquisition Date: 2011-02-10