Assortative Mating-A Missing Piece in the Jigsaw of Psychiatric Genetics.

Abstract

The topicof assortative (nonrandom)matingmight seemesoteric or even salacious. For example, in lectures you have to point out to students that random mating is not about promiscuity. In this issue of JAMA Psychiatry, Nordsletten and colleagues1 report the first general population study to date of assortativemating for psychiatric disorders, which may help to solve 3 puzzles in psychiatric genetics: Why are psychiatric disorders so highly heritable when they are associatedwith reduced fecundity?Whyare somepsychiatric disorders somuchmorehighlyheritable thanothers?Why is there so much genetic comorbidity across psychiatric disorders? The research capitalizes on the powerful population registers in Sweden, which contain diagnostic information, includingpsychiatric diagnoses, onall individuals admitted toSwedish hospitals since 1973. The registers yield huge samples of cases (eg, more than 70000 individuals diagnosed as having schizophrenia). Using other registers to track couples via their children, the investigators were able to measure assortative mating levels within and between 11 psychiatric disorders. Althoughyoucanseeassortativemating forphysical traits, likeheight andweight,withyourowneyes, the correlationbetween spouses is only approximately0.20 for these traits. For personality, assortative mating is even lower at approximately 0.10. In contrast, Nordsletten and colleagues1 find an amazing amount of assortativematingwithin psychiatric disorders. Spouse tetrachoric correlations are greater than 0.40 for attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia. The next highest spouse correlation emerged for substance abuse (range, 0.36-0.39). Assortative mating was significant but far less substantial for other disorders, such as affective disorders (range, 0.14-0.19). Thesefindingsare intriguing inrelationtothefirst2puzzles about heritability of psychiatric disorders. The significance of assortativemating for polygenic traits, suchaspsychiatric disorders, is that it increases additive genetic variance generation after generation until equilibrium is reached. Additive genetic variance refers to genetic effects that breed true from parents to offspring because they involve independent effects of alleles that “addup.”This additivevariance is in contrast tononadditiveeffectsofdominancewithina locusorepistasis across loci in which the effects of alleles or loci interact. Unlike inbreeding, which reduces heterozygosity across the genome, assortative mating is trait specific. That is, it increasesadditivegeneticvariance (changinggenotypic frequencies but not allelic frequencies) only for genes associatedwith the trait forwhichmatesassort andother traits genetically correlated with that trait. As a consequence, assortative mating increases the contribution of additive genetic variance (narrowheritability) for any trait on which it acts. This boost to heritability from assortative mating could help to explain why psychiatric disorders have such high heritability despite reduced fecundity. Assortative mating could also contribute to the second question about why some psychiatric disorders—most notably,ADHD,ASD,andschizophrenia—aremoreheritable in twin studies than other disorders, such as the affective disorders. The answer from the article by Nordsletten and colleagues1 could be that the former show twice asmuch assortativemating as the latter. However, these solutions are not quite as clear cut as they may seem. The argument goes that the abundant assortative mating for ADHD, ASD, and schizophrenia increases additive genetic variance. However, twin studies suggest that nonadditive genetic influence is greater for these same 3 disorders than for other disorders in that dizygotic twins aremuch less thanhalf as similar asmonozygotic twins.2Most notably, concordance forASD is approximately60%formonozygotic twins and approximately 5% for dizygotic twins.2 Nonetheless, it is possible that these 3 disorders are so highly heritable because they include injections of both additive genetic variance from assortative mating and unusually high nonadditive genetic variance. Without assortative mating, these disorders might show little additive genetic variance. Another issue that needs to be resolved involves DNAbased heritability estimates, which only detect additive genetic variance. From the findings by Nordsletten and colleagues1 alone, one would predict that DNA-based heritability estimates should be greater for ADHD, ASD, and schizophrenia than for affective disorders, but the results so far suggest otherwise.3 Nonetheless, the dust is yet to settle on the explosionof researchestimatingheritabilityusingDNAalone. It is crucial to resolve this issue because genome-wide association studies typically only search for additive genetic effects. In other words, additive genetic variance is the ceiling both for DNA-based heritability estimates and for identifying DNA variants in genome-wide association studies. Understanding its extent and causes is key to psychiatric genetics research. The third genetic puzzle is why there is so much genetic comorbidity across psychiatric disorders. A major discovery from genome-wide association studies is that genetic variRelated article page 354 Opinion