For couples seeking to conceive, offer advice on reducing the risk of schizophrenia in their child

I explained to them that schizophrenia is a neurodevelopmental syndrome that comprises hundreds of different disorders of genetic or non-genetic etiology, all of which share a similar psychotic phenotype. Although the various genetic causes of schizophre­nia are difficult to prevent—but may be prevented in the future with epi­genetic techniques—the many non-genetic (environmental) pathways to schizophrenia can be avoided to significantly reduce the incidence of schizophrenia by 40% to 50%, accord­ing to some estimates.

I will share what I told this couple, because even couples without any family history of psychosis may have a child who develops schizophrenia because of a variety of environmental risk factors.

Genetic risk factors
One-half of the 20,000 genes in the 23 chromosomes of the human genome participate in constructing and sculpt­ing the extremely intricate and com­plex human brain. There are many ways that genetic factors can increase the risk of schizophrenia,¹ and only some are transmitted by parents:

Risk genes. More than 30 risk genes have been identified as heritable in schizophrenia. They are spread over many chromosomes and more are likely to be discovered. Most of those risk genes regulate glutamate— not dopamine—pathways, and each increases the risk by 2% to 4%.

Copy number variations (CNVs) are pro­duced via meiosis mishaps, where 1 or 3 alleles of certain genes are formed instead of the usual 2. A high frequency of CNVs have been found in schizophrenia com­pared with the general population—but also are found in autism and bipolar disorders—and are believed to disrupt brain development in various ways.

De novo mutations. Recent studies on large samples of people with schizo­phrenia (50,000 to 100,000) uncovered a much higher rate of mutations (some code for proteins while others are non­sense mutations that code for noth­ing). Obviously, these mutations led to anomalous neurodevelopment.

There are hundreds, maybe thou­sands, of genetic subtypes within the schizophrenia syndrome. Advances in epigenetics, which allow silencing of culprit genes or overexpression of protective genes, one day may enable psychiatric geneticists to prevent schizo­phrenia in fetuses at risk.

Non-genetic risk factors
Just as with the genetic patho-genic heterogeneity, the schizo­phrenia syndrome can be caused by numerous environmental adverse events,² many of which can be avoided, including:

Older paternal age (>45) at time of conception doubles or triples the risk of schizophrenia³ as well as autism and bipolar disorder. Aging sperm are associated with a higher rate of DNA fragmentation and genetic mutations.

Prenatal complications, especially during the second trimester when CNS development takes place. These adverse prenatal events skew fetal brain development to produce psy­chosis in adulthood and can be mini­mized with optimal prenatal care, which sadly is lacking among the poor. These include:
• Vaginal infections before preg­nancy,⁴ such as herpes simplex virus, can cause fetal brain inflammation and increased risk of schizophrenia.
• Infections during pregnancy— whether bacterial, viral, or proto­zoan (Toxoplasma gondii)—have been shown to significantly increase the risk of schizophrenia in offspring.⁵ An increase in serum C-reactive protein during pregnancy also is a biomarker of increased risk.
• Poor diet, especially starva­tion, can double or triple the risk of schizophrenia.
• Vitamin deficiency, especially folate and vitamin D, are critical for normal brain development.⁶ Vitamin D is vital to mitigate neuroinflammation.
• Smoking before and during pregnancy.⁴
• Medical illness during preg­nancy, especially gestational diabetes, increases the risk of schizophrenia in the fetus by 800%.⁷
• Severe stress during pregnancy, such as the death of the spouse, dou­bles the risk of schizophrenia.²
• Schizophrenia risk is 400% to 500% higher among those born and raised in an urban area, compared with a rural area.⁸
• Babies born in northern latitudes, such as in Sweden, Norway, or Canada, have a 10-fold risk of schizophrenia in adulthood compared with babies born near the equator.⁶ This has been attrib­uted to lack of sunshine and the risk of severe vitamin D deficiency in north­ern latitudes.
• High maternal body mass index during the first trimester⁷ increases the child’s risk of schizophrenia.
• Low number of prenatal vis­its is associated with higher risk of schizophrenia.
• Obstetric complications that cause hypoxia and a low Apgar score after birth increase the risk of schizophrenia. This includes long labor, cord around the neck, meco­nium spillage into the amniotic fluid, and mechanical injury with forceps delivery.
• Infection in the newborn shortly after birth.

Severe physical or sexual abuse before age 5 is associated with increased risk of schizophrenia in adulthood.² This may be because of stress-induced epigenetic mechanisms (silencing or overexpressing certain genes).

Migration has been shown to increase the risk of schizophrenia by 3 to 5 fold. The exact reason is unclear, but it could be a combination of social stress, exposure to new types of germs, less sunshine, and even a different diet.