Wednesday, March 26, 2008

Advancing Paternal Age and the Risk of Schizophrenia

Third, schizophrenia is associated with older paternal age, and older paternal age is associated with increased rates of de novo germline mutations. Thus, new individually rare severe mutations in genes related to brain functioning or neural development may be responsible for a portion of cases of schizophrenia.
Any gene harboring one disease-related mutation is likely to harbor more than one mutation


Vol. 58 No. 4, April 2001 Archives

Advancing Paternal Age and the Risk of Schizophrenia
Dolores Malaspina, MD; Susan Harlap, MBBS; Shmuel Fennig, MD; Dov Heiman, MPH; Daniella Nahon, BA; Dina Feldman, MA; Ezra S. Susser, MD, PhD

Arch Gen Psychiatry. 2001;58:361-367.

Background A major source of new mutations in humans is the male germ line, with mutation rates monotonically increasing as father's age at conception advances, possibly because of accumulating replication errors in spermatogonial cell lines.

Method We investigated whether the risk of schizophrenia was associated with advancing paternal age in a population-based birth cohort of 87 907 individuals born in Jerusalem from 1964 to 1976 by linking their records to the Israel Psychiatric Registry.

Results Of 1337 offspring admitted to psychiatric units before 1998, 658 were diagnosed as having schizophrenia and related nonaffective psychoses. After controlling for maternal age and other confounding factors (sex, ethnicity, education [to reflect socioeconomic status], and duration of marriage) in proportional hazards regression, we found that paternal age was a strong and significant predictor of the schizophrenia diagnoses, but not of other psychiatric disorders. Compared with offspring of fathers younger than 25 years, the relative risk of schizophrenia increased monotonically in each 5-year age group, reaching 2.02 (95% confidence interval, 1.17-3.51) and 2.96 (95% confidence interval, 1.60-5.47) in offspring of men aged 45 to 49 and 50 years or more, respectively. Categories of mother's age showed no significant effects, after adjusting for paternal age.

Conclusions These findings support the hypothesis that schizophrenia may be associated, in part, with de novo mutations arising in paternal germ cells. If confirmed, they would entail a need for novel approaches to the identification of genes involved in schizophrenia.

From the Department of Psychiatry/New York State Psychiatric Institute, Columbia University, New York (Drs Malaspina and Susser); Department of Obstetrics and Gynecology, New York University School of Medicine, New York (Dr Harlap); Shalvata Mental Health, Ministry of Mental Health, Even-Yehuda, Israel (Dr Fennig and Mr Heiman); and Mental Health Services Section, Israel Ministry of Health, Tel Aviv (Mss Nahon and Feldman).

Corresponding author: Dolores Malaspina, MD, New York State Psychiatric Institute, 1051 Riverside Dr, New York, NY 10032 (e-mail:


Nat Rev Genet. 2000 Oct;1(1):40-7.Related Articles, Links
The origins, patterns and implications of human spontaneous mutation.

Crow JF.

Genetics Department, University of Wisconsin, Madison, Wisconsin 53706, USA.

The germline mutation rate in human males, especially older males, is generally much higher than in females, mainly because in males there are many more germ-cell divisions. However, there are some exceptions and many variations. Base substitutions, insertion-deletions, repeat expansions and chromosomal changes each follow different rules. Evidence from evolutionary sequence data indicates that the overall rate of deleterious mutation may be high enough to have a large effect on human well-being. But there are ways in which the impact of deleterious mutations can be mitigated.

Publication Types:

PMID: 11262873 [PubMed - indexed for MEDLINE]

IntroductionSegmental duplications (also termed “low-copy repeats”) are blocks of DNA that range from 1 to 400 kb in length, occur at more than one site within the genome, and typically share a high level of (>90%) sequence identity (reviewed by Eichler [2001]). Both in situ hybridization and in silico analyses have shown that ~5% of the human genome is composed of duplicated sequence (Cheung et al. 2001; Bailey et al. 2002; Cheung et al. 2003; She et al. 2004a), and many studies have noted a significant association between the location of segmental duplications and regions of chromosomal instability or evolutionary rearrangement (Ji et al. 2000; Samonte and Eichler 2002; Armengol et al. 2003; Locke et al. 2003a, 2003b; Bailey et al. 2004). Indeed, segmental duplications have been implicated as the probable mediators of >25 recurrent genomic disorders (reviewed by Stankiewicz and Lupski [2002]). Molecular studies have shown that the presence of large, highly homologous flanking repeats predisposes these regions to recurrent rearrangement by nonallelic homologous recombination, resulting in deletion, duplication, or inversion of the intervening sequence (Chance et al. 1994; Shaw et al. 2002).

A growing body of evidence now suggests that the duplication architecture of the genome may also mediate normal variation. The existence of large genomic polymorphisms, originally termed “heteromorphisms” or “euchromatic variants,” has been recognized since the advent of high-resolution cytogenetic banding techniques (summarized at the Chromosome Anomaly Register Web site). With the use of more-targeted molecular analyses, a number of submicroscopic polymorphic rearrangements between homologous blocks of sequence have been identified in the normal population (Siniscalco et al. 2000; Sprenger et al. 2000; Giglio et al. 2001; Osborne et al. 2001; Gimelli et al. 2003; Skaletsky et al. 2003). Recently, the use of methods such as array comparative genomic hybridization (array CGH) and representational oligonucleotide microarray analysis (ROMA) have revealed the presence of numerous copy-number polymorphisms (CNPs) in the human genome and have suggested an enrichment of segmental duplications associated with these variants (Iafrate et al. 2004; Sebat et al. 2004). However, these studies used arrays with either limited genomic coverage or limited resolution with respect to regions of segmental duplication, and even current tiling-path arrays with >30,000 BAC clones (Ishkanian et al. 2004) do not achieve complete coverage of regions rich in segmental duplications (Z.C. and E.E.E., unpublished data).

Because regions flanked by segmental duplications are susceptible to rearrangement by nonallelic homologous recombination, we hypothesized that these regions represent potential hotspots of genomic instability that are prone to copy-number variation. It has been shown that several factors—including the length, sequence identity, and orientation of and the distance between duplications—influence the probability of meiotic misalignment (Stankiewicz and Lupski 2002). Most of the blocks of duplicated sequence that have been implicated in known genomic disorders are large (10–400 kb in size) and have >96% sequence identity. This level of sequence sharing between intrachromosomal sites provides ample substrate for aberrant recombination, on the basis of the estimated minimal efficient-processing segment length (Waldman and Liskay 1988). In general, the larger and more homologous the block of duplicated sequence is, the more frequently sporadic segmental aneusomy events occur. For example, the most frequently occurring microdeletion syndrome (velocardiofacial and DiGeorge syndromes; frequency 1/3,000) occurs between blocks of duplications that are in excess of 300 kb in length and that share 99.7% sequence identity (Edelmann et al. 1999; Shaikh et al. 2000).

Thus, a review of the recurrent genomic disorders characterized to date suggests a strategy for the identification of novel regions of genomic instability. With a focus on regions flanked by intrachromosomal duplications that are >10 kb in length, share >95% sequence identity, and span from 50 kb to 10 Mb of intervening sequence (Stankiewicz and Lupski 2002), novel sites of genomic variation may be uncovered. On the basis of these criteria, in silico analysis of the human genome defines a map of potential rearrangement hotspots (Bailey et al. 2002). In total, 130 regions—covering 274 Mb, or ~10% of the entire genome—are flanked by intrachromosomal duplications whose characteristics suggest a potential predisposition to genomic instability. Whereas 25 of these regions are associated with known genomic disorders, the remainder represent novel sites whose genomic architecture is susceptible to either polymorphic or disease-causing rearrangement. We have constructed a custom BAC array, termed the “segmental duplication microarray” (SD microarray), specifically targeted to these rearrangement hotspots, and we used it to investigate copy-number variation in a panel of ethnically diverse normal individuals. We report the discovery of numerous novel CNPs distributed throughout the human population and demonstrate an enrichment of copy-number variation in regions of the genome flanked by segmental duplications.

King MC, Ahsan H, Susser E. Designs for the genomic era. In: Susser E, Schwartz S, Morabia A, Bromet EJ, eds. Psychiatric Epidemiology: Searching for the Causes of Mental Disorders. New York, NY: Oxford University Press; 2006



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