7 June 2005. Children born and raised in cities grow up to develop schizophrenia at a higher rate than their country-dwelling counterparts (Pedersen and Mortensen, 2001). While the epidemiological evidence implicates environmental factors, no specific exposures have been identified that can explain the urban-rural difference. But because the urban environment acts on both children and their families, it stands to reason that environmental effects act on the level of the family to contribute to the increased risk of schizophrenia in cities.
To determine if family effects have a role in raising schizophrenia risk for urban dwellers, Carsten Pedersen and Preben Bo Mortensen from the National Centre for Register-based Research at the University of Aarhus, Denmark, designed an ingenious epidemiological study. Using data from nationwide Danish registers, they asked if the birthplace (whether urban, rural, or in-between) of an older sibling is associated with the risk of schizophrenia in the next-born child of the family. If the answer turned out to be no, they reasoned, that would suggest that urban factors acted mainly on individuals. But if the answer was yes, it would indicate that the urban environment could act on families to somehow increase the likelihood of their child having the disease.
According to results Pedersen and Mortensen published in the June issue of the American Journal of Epidemiology, the answer is yes—the birth locale of an older sibling contributes to the risk of schizophrenia just as much as the birthplace of an affected individual does. By using the degree of urbanization of the older sibling’s birthplace as a proxy for the urbanization of the family, the study reveals that the negative effects of the urban environment can accrue for years before conception. The effects persist, too, even if the family leaves the city: the analysis shows that the risk associated with an older sibling’s urban birth persists even if the next child is born in the country.
While the work does not identify the environmental factors themselves, it should guide researchers to investigate more family-related risks in their search for causes of the urban-rural differences in schizophrenia.
The study population consisted of all people born in Denmark between 1956 and 1986 who had at least one older full sibling. By cross-checking birth registries and medical data on more than 700,000 people, the researchers identified 2,720 cases of schizophrenia between 1970 and 2001. For their analysis, the degree of urbanization of each person’s place of birth was assigned to one of three levels (capital, provincial, or rural).
The analysis showed that the location of an older sibling’s birth independently affected the risk of schizophrenia among the younger siblings, after adjustment for age, gender, family history of mental illness, and other confounding factors. For example, among people born in rural areas, the risk of schizophrenia was higher if their older sibling was born in an urban area (adjusted risk ratio 1.61, 95 percent confidence interval, 1.25-2.05). Individual factors were important, too—if the affected subject was born in an urban area, the place of birth of their older sibling had no effect. The authors summarize by writing, ”These results suggest that individual’s place of birth (and upbringing) and nearest older sibling’s place of birth were virtually interchangeable in terms of schizophrenia risk—that is, both variables contribute to the risk of schizophrenia.”
The results point to the family situation as an important locus for environmental insults, but what kinds of exposure could cause the differences observed? Parental education level is one possibility to explain family-related risk, but Pedersen and Mortensen say the reported effects are too small to be the only explanation for their findings. They suggest several possibilities, including maternal lead exposure, toxoplasmosis, or infections in siblings that would affect fetal development or be transmitted years later.
One intriguing possibility to explain these results is a twist on selective migration—the idea that individuals at risk for schizophrenia preferentially migrate to urban areas, while mentally healthy people do not. Selective migration of individuals clearly cannot explain the higher risk of schizophrenia among children born in the city. But selective migration operating at the level of families might. In that case, families carrying some unknown risk for schizophrenia might also tend to settle in urban areas, where they raise at-risk children. To advance understanding the urban-rural differences, direct measurements of genes and environmental factors associated with schizophrenia risk will be needed, Pedersen and Mortensen conclude.
In an accompanying invited commentary, Dana March and Ezra Susser of Columbia University, New York, write that the work of Pedersen and Mortensen, “exemplifies the possibilities for schizophrenia research.” By reaching beyond looking at individual characteristics to looking at family factors, the study recognizes that environmental factors operate at many levels, where they interact with genetic factors in complex ways.
March and Susser have dubbed this integrative mode “eco-epidemiology” which promotes sharply focused studies to pull apart and then put back together the social, environmental, and genetic causes of disease.—Pat McCaffrey.
Pedersen CB, Mortensen PB. Are the Cause(s) Responsible for Urban-Rural Differences in Schizophrenia Risk Rooted in Families or in Individuals? Am J Epidemiol. 2006 Jun 1;163(11):971-8. Epub 2006 May 4. Abstract
March D, Susser E. Invited commentary: taking the search for causes of schizophrenia to a different level. Am J Epidemiol. 2006 Jun 1;163(11):979-81. Epub 2006 May 4. Abstract