Schizophrenia is a complex mental disorder characterized by persistent delusions, hallucinations, and disorganized thinking or behavior, typically emerging in late adolescence or early adulthood. The causes of schizophrenia are not fully understood, but current research points to a combination of genetic and environmental factors. The question of whether the risk for schizophrenia is inherited more from the mother or the father requires looking beyond simple Mendelian inheritance to consider the interplay of genes, parental age effects, and the prenatal environment.
The Heritability of Schizophrenia
Genetic factors play a significant role in determining an individual’s risk for developing schizophrenia, with estimates of heritability ranging between 70% and 80%. This figure suggests that a large portion of the individual differences in risk is associated with genetic makeup. The foundational evidence for this comes from classic genetic studies, such as twin and adoption studies.
Twin studies consistently show a much higher concordance rate for identical (monozygotic) twins, who share 100% of their DNA, compared to fraternal (dizygotic) twins, who share about 50% of their DNA. If one identical twin has schizophrenia, the chance that the other twin will also be affected is approximately 40% to 50%, whereas the risk for a fraternal twin is significantly lower, around 7% to 17%. Adoption studies further support this genetic link by showing that children who are separated from their biological parents and raised in a different family environment still have a higher risk of developing the disorder if a biological parent was affected. Specifically, children whose biological mothers had schizophrenia were found to be more likely to develop the condition compared to control groups, even when raised by adoptive parents who did not have the disorder.
Parental Age and Risk Factors
The risk for schizophrenia is polygenic, meaning it involves the transmission of many genes from both parents, and is generally not parent-specific. However, two distinct mechanisms relating to parental source—one genetic and one environmental—introduce differences in risk related to the age and health of each parent. The single most common risk factor for schizophrenia is having a first-degree relative with the disorder, which increases the risk substantially compared to the general population risk of about 0.3% to 0.7%.
The age of the father has been consistently linked to an increased risk of schizophrenia in the offspring, a phenomenon known as the paternal age effect. This increased risk is thought to be primarily due to the accumulation of de novo mutations in the male germline, or sperm cells, as men age. Unlike eggs, sperm cells undergo continuous division throughout a man’s life, and each division carries a risk of generating new, random mutations not present in the father’s own DNA. These new mutations can be passed on to the child and may contribute to the overall genetic liability for schizophrenia.
Risk factors associated with the mother are primarily related to the prenatal environment, which is separate from genetic inheritance but still affects the developing fetus. Maternal health during pregnancy can influence the child’s neurodevelopment, with factors like prenatal maternal stress, malnutrition, and infection contributing to risk. For example, exposure to certain infections or severe stress during gestation can alter fetal neurodevelopment, potentially through an increase in pro-inflammatory cytokines. While the mother genetically contributes 50% of the child’s genes, the maternal contribution to risk also encompasses the critical uterine environment, which can be affected by factors like maternal obesity, poor nutrition, and obstetric complications.
The Mechanisms of Genetic Transmission
The transmission of schizophrenia risk involves a highly complex genetic architecture that is best described by a polygenic model. This model suggests that the disorder is not caused by a single gene but rather by the combined effect of hundreds, or even thousands, of common genetic variants, each contributing a very small amount to the overall risk. The total genetic liability an individual inherits can be quantified using a Polygenic Risk Score (PRS), which sums up the risk-increasing alleles across the genome.
Beyond the common variants, rare, high-impact mutations also play a role in a smaller percentage of cases. One such type of mutation is Copy Number Variations (CNVs), which are structural changes in the DNA that involve the deletion or duplication of large segments of the genome. These CNVs can sometimes increase the risk of developing schizophrenia by as much as 20-fold and are associated with known genomic disorders. An inverse relationship has been observed, where individuals with highly penetrant CNVs, such as the 22q11.2 deletion, tend to have a lower overall Polygenic Risk Score from common variants, suggesting that a major mutation can sometimes override the need for a high number of small-effect variants to reach the threshold for the disorder.
Non-Genetic Factors and Their Interaction
Since the concordance rate for identical twins is not 100%, environmental factors must interact with genetic predisposition to trigger the onset of the disorder. This interaction is explained by the diathesis-stress model, where a genetic vulnerability (diathesis) requires an environmental stressor to manifest as the illness. These non-genetic factors do not cause schizophrenia on their own but can act as triggers for those who are already genetically vulnerable.
Specific examples of environmental stressors include developmental and obstetric complications such as hypoxia, or a lack of oxygen, during birth. Early life trauma, including childhood adversity and severe stress, is also considered a contributing factor. Furthermore, substance use, particularly cannabis use during adolescence, has been associated with an elevated risk of the disorder, especially in individuals with an existing genetic vulnerability. Other factors, such as being raised in an urban environment or experiencing social isolation, also contribute to the overall environmental risk profile.
Assessing Individual Risk
Assessing the risk of developing schizophrenia for an individual is based largely on the degree of genetic relatedness to an affected family member. The risk is highest for first-degree relatives, which include parents, full siblings, and children of an affected person. While the risk for the general population is less than 1%, the risk increases to approximately 6.5% for a first-degree relative and around 13% if one parent is affected.
The risk drops significantly for second-degree relatives, such as aunts, uncles, grandparents, and half-siblings, and decreases further for third-degree relatives like first cousins. However, even with a strong family history, the absolute risk for most individuals remains low, emphasizing that genetic predisposition is not a guarantee of developing the condition. For individuals with a significant family history of the disorder, seeking genetic counseling can provide a more personalized assessment of risk and discuss the latest scientific understanding of the complex genetic and environmental influences.
Non-Genetic Factors and Their Interaction
Since the concordance rate for identical twins is not 100%, environmental factors must interact with genetic predisposition to trigger the onset of the disorder. This interaction is explained by the diathesis-stress model, where a genetic vulnerability (diathesis) requires an environmental stressor to manifest as the illness. These non-genetic factors do not cause schizophrenia on their own but can act as triggers for those who are already genetically vulnerable.
Specific examples of environmental stressors include developmental and obstetric complications such as hypoxia, or a lack of oxygen, during birth. Early life trauma, including childhood adversity and severe stress, is also considered a contributing factor. Furthermore, substance use, particularly cannabis use during adolescence, has been associated with an elevated risk of the disorder, especially in individuals with an existing genetic vulnerability. Other factors, such as being raised in an urban environment or experiencing social isolation, also contribute to the overall environmental risk profile.
Assessing Individual Risk
Assessing the risk of developing schizophrenia for an individual is based largely on the degree of genetic relatedness to an affected family member. The risk is highest for first-degree relatives, which include parents, full siblings, and children of an affected person. While the risk for the general population is less than 1%, the risk increases to approximately 6.5% for a first-degree relative and around 13% if one parent is affected.
The risk drops significantly for second-degree relatives, such as aunts, uncles, grandparents, and half-siblings, and decreases further for third-degree relatives like first cousins. However, even with a strong family history, the absolute risk for most individuals remains low, emphasizing that genetic predisposition is not a guarantee of developing the condition. For individuals with a significant family history of the disorder, seeking genetic counseling can provide a more personalized assessment of risk and discuss the latest scientific understanding of the complex genetic and environmental influences.