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Microcephaly Genes and Risk of Late-Onset Alzheimer Disease

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ORIGINAL ARTICLE Microcephaly Genes and Risk of Late-onset Alzheimer Disease Deniz Erten-Lyons, MD,*w Beth Wilmot, PhD,zy Pavana Anur, BS,z Shannon McWeeney, PhD,zyJ Shawn K. Westaway, PhD,w Lisa Silbert, MD,w Patricia Kramer, PhD,w and Jeffrey Kaye, MD*w Alzheimer’s Disease Neuroimaging Initiative ratio=3.41; confidence interval, 1.77-6.57). However, this associa- Abstract: Brain development in the early stages of life has been tion was not replicated using another case-control sample research suggested to be one of the factors that may influence an individual’s participants from the Alzheimer Disease Neuroimaging Initiative. risk of Alzheimer disease (AD) later in life. Four microcephaly We conclude that the common variations we measured in the 4 genes, which regulate brain development in utero and have been microcephaly genes do not affect the risk of AD or that their effect suggested to play a role in the evolution of the human brain, were size is small. selected as candidate genes that may modulate the risk of AD. We examined the association between single nucleotide polymorphisms Key Words: Alzheimer disease, microcephaly genes, cognitive tagging common sequence variations in these genes and risk of AD reserve in two case-control samples. We found that the G allele of (Alzheimer Dis Assoc Disord 2011;25:276–282) rs2442607 in microcephalin 1 was associated with an increased risk of AD (under an additive genetic model, P=0.01; odds Received for publication June 2, 2010; accepted December 2, 2010. enetics has been suggested to play a role in variations From the *Portland Veterans Affairs Medical Center; wDepartment of Gin cognitive function in late life.1 One way in which Neurology; zOregon Clinical and Translational Research Center; genes may play a role in cognitive function in late life is yDivision of Bioinformatics and Computational Biology, Depart- through providing an “initial endowment” that is more ment of Medical Informatics and Clinical Epidemiology; and JDivision of Biostatistics, Department of Public Health and resistant to age-related changes. This initial endowment, or Preventative Medicine, Oregon Health and Science University, cognitive reserve, may include both functional and struc- Portland, OR. tural brain features (such as cerebral size), which may Supported by Merit Review Grant and Research Career Development increase the threshold for responses to brain insult.2 We Award, Office of Research and Development, Department of Veterans Affairs, National Institutes of Health (AG08017, MO1 hypothesize that variations in genes regulating brain size RR000334, UL1 RR024140), Alzheimer Tax Check-off Grant. during neurodevelopment may play a role in individual Data collection and sharing for this project was funded by the susceptibility to cognitive decline by modulating the brain Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National size. This study examines whether 4 microcephaly genes Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical (abnormal spindle-like microcephaly-associated (ASPM)), Imaging and Bioengineering, and through generous contributions microcephalin 1 (MCPH1), centromeric protein J (CENPJ), from the following: Abbott; AstraZeneca AB; Bayer Schering and cyclin-dependent kinase 5 regulatory subunit-asso- Pharma AG; Bristol-Myers Squibb; Eisai Global Clinical Devel- ciated protein 2 (CDK5RAP2)) play a role in late-life risk of opment; Elan Corporation; Genentech; GE Healthcare; GlaxoS- mithKline; Innogenetics; Johnson and Johnson; Eli Lilly and Co.; Alzheimer disease (AD). Medpace, Inc.; Merck and Co., Inc.; Novartis AG; Pfizer Inc.; F. Mutations in these 4 genes cause reduced brain size Hoffman-La Roche; Schering-Plough; Synarc, Inc.; and nonprofit and head circumference and mental retardation.3 The partners the Alzheimer’s Association and Alzheimer’s Drug microcephaly genes are expressed in the embryonic brain, Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are especially in the ventricular zone, during cerebral cortical facilitated by the Foundation for the National Institutes of Health neurogenesis.4 The timing and location of their expres- (www.fnih.org). The grantee organization is the Northern Califor- sion suggest that they play a role in regulating neurogenic nia Institute for Research and Education, and the study is mitosis before birth.4 Sequence comparisons among pri- coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated mate species suggest that microcephaly genes experienced by the Laboratory for Neuro Imaging at the University of adaptive evolution due to positive selection5–9; rare variants California, Los Angeles. This research was also supported by in these genes increased in frequency over time due to an NIH grants P30 AG010129, K01 AG030514, and the Dana advantageous phenotype they provide. Foundation. The Alzheimer’s Disease Neuroimaging Initiative: Data used in the There is also evidence that 2 haplotype-defining single preparation of this article were obtained from the ADNI database nucleotide polymorphisms (SNPs) in ASPM and MCPH1, (www.loni.ucla.edu/ADNI). As such, the investigators within the rs41310927 and rs930557, respectively, have continued to ADNI contributed to the design and implementation of ADNI and/ work under positive selection, beyond the emergence of the or provided data but did not participate in the analysis or the 6–8 writing of this report. Complete listing of ADNI investigators anatomically modern humans. Earlier studies imply that is available at: www.loni.ucla.edu\ADNI\Collaboration\ADNI\ the positive selection in the microcephaly genes may be Manuscript\Citations.pdf related to an advantageous brain-associated phenotype, Reprints: Deniz Erten-Lyons, MD, National Institute of Aging, Layton such as brain size, cognition, personality, motor control, or Aging and Alzheimer’s Disease Center, 3181 SW Sam Jackson Park Road CR 131, Portland, OR 97239 (e-mail: [email protected]). susceptibility to neurological or psychiatric disease. Several Copyright r 2011 by Lippincott Williams & Wilkins studies have specifically investigated a relationship between 276 | www.alzheimerjournal.com Alzheimer Dis Assoc Disord Volume 25, Number 3, July–September 2011 Alzheimer Dis Assoc Disord Volume 25, Number 3, July–September 2011 Microcephaly Genes and Risk of Late-onset AD such phenotypes and some or all of the microcephaly (4) had no first-degree family history of AD (to ensure that genes.10–16 Most of the studies to date have found no none of the participants had an undescribed genetic association between brain-related phenotypes (brain vo- predilection for AD that could confound the analyses); lumes, general cognitive ability, head circumference, or risk and (5) were either >69 years old (for the first discovery of schizophrenia) and these 2 polymorphisms. Only 2 case-control sample) or were >64 years old (for the second studies have found associations between common SNPs in discovery case-control sample) at the onset of symptoms MCPH1, CDK5RAP2, or ASPM and brain volumes in a for cases or at the last evaluation for controls. When sex-specific manner.13,16 One of these studies also sought comparing basic demographics between cohorts to ensure for an association between 2 SNPs in CDK5RAP2 and that cohort differences were not confounding the analysis, it schizophrenia, bipolar spectrum disorder, AD, and mild became evident that participants from the memory clinic cognitive impairment (MCI) and found no association.16 were younger than the participants in the longitudinal aging In this study, we examined the association between the studies. Therefore, an age criteria was added. This criteria microcephaly genes and risk of AD using tag SNPs was reduced to >64 years in the second case-control sample covering all 4 genes. To test our hypothesis, we completed to increase the sample size. Those with a CDR of 0.5 and not a 2-step study. In the discovery step, 2 related but separate meeting diagnostic criteria for AD were excluded. case-control studies were carried out: first the association between SNPs in ASPM and AD risk was examined. SNP Selection and Genotyping Later, the association between MCPH1, CDK5RAP2, and A tag SNP panel was generated using data obtained CENPJ SNPs and AD risk was examined in a slightly from a pilot study24 and the HapMap CEU (Utah larger case-control sample. Data from the Alzheimer’s Residents with Northern and Western European Ancestry) Disease Neuroimaging Initiative (ADNI) were used to population.25 In the pilot study, coding regions of ASPM validate the findings from the discovery step. were resequenced in an independent sample of 59 partici- pants (30 cases and 29 controls) from our study population. METHODS We determined that the frequencies of the ASPM SNPs in The Portland Veterans Affairs Medical Center Institu- our population were comparable with the HapMap CEU tional Review Board approved this study. population. Therefore, tag SNPs spanning the entire ASPM gene were selected using Haploview 3.2 based on data Description of Participants obtained from the HapMap CEU population. Haploview 26 Participants were selected from longitudinal aging uses a method that is identical to the program Tagger. A studies conducted at the Oregon Alzheimer Disease Center pair-wise tagging method using single markers with thresh- 2 (OADC). These
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