Abstract
Background
Schizophrenia is highly heritable as shown by MZ/DZ twin comparisons and is calculated to be at about 80%, although if familial transmission were Mendelian, it would be considered 100%. Since the field of genetics has produced the needed technology to examine DNA at the molecular level (beginning in the 1980’s), researchers have attempted to find a major gene for schizophrenia, without success. Once it was realized that the most likely underlying genetic mechanism is multiple gene variants of small individual effect, it was realized that large sample sizes would be needed to detect them. Thus, international collaborations were organized, the most important being the Psychiatric Genomics Consortium (PGC), now over 900 investigators having accumulated over 100,000 individual DNA samples.
Methods
The most current analyses of these data comparing patients with schizophrenia to controls has now yielded over 250 genome-wide significant loci producing modest elevation in the risk for schizophrenia (unpublished data presented at the World Congress of Psychiatric Genetics 10/18; https://www.med.unc.edu/pgc/pgc-workgroups). However, when taken together the heritability due to these loci or SNPs (SNP-Based Heritability) is calculated to be only about 23% (Lee et al., 2012). The difference between the overall heritability and the contribution of modest effect loci is thus 57%. This latter figure is the so called “missing heritability and likely due to mutations of large affect that segregate with illness within some families. Recently we performed a sequencing study of families multiply affected with schizophrenia.
Results
We found mutations present in all affecteds and no unaffecteds in 7 of 9 families (Homann et al., 2016). These mutations were unique to each family but were within genes relevant to neuronal differentiation and migration, such as the SHANK-2 gene in one large family. Other investigators have similar findings in different families.
Discussion
In summary, the genetic basis for schizophrenia is heterogeneous, while some individuals inherit a large number of common risk genes, others inherit mutations that are of high risk within their individual families. This heterogeneity makes it unlikely that molecular genetics will be useful for prediction of who will develop schizophrenia, but on the other hand, classes of genes involved may lead to novel drug targets for developing future medications.
References:
Lee SH, DeCandia TR, Ripke S, Yang J; Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ); International Schizophrenia Consortium (ISC); Molecular Genetics of Schizophrenia Collaboration (MGS), Sullivan PF, Goddard ME, Keller MC, Visscher PM, Wray NR. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet. 2012 Feb 19;44(3):247–50. doi: 10.1038/ng.1108.
Homann OR, Misura K, Lamas E, Sandrock RW, Nelson P, McDonough SI, DeLisi LE. Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness..Mol Psychiatry. 2016; 21: 1690–1695. doi: 10.1038/mp.2016.24. PMID: 27001614