Neanderthal‐derived genetic variation in living humans relates to schizophrenia diagnosis, to psychotic symptom severity, and to dopamine synthesis

Abstract

Schizophrenia has been hypothesized to be a human-specific condition, but experimental approaches to testing this idea have been limited. Because Neanderthals, our closest evolutionary relatives, interbred with modern humans prior to their disappearance from the fossil record, leaving a residual echo that survives in our DNA today, we leveraged new discoveries about ancient hominid DNA to explore this hypothesis in living people in three converging ways. First, in four independent case-control datasets totaling 9,362 individuals, individuals with schizophrenia had less Neanderthal-derived genetic variation than controls (p = .044). Second, in 49 unmedicated inpatients with schizophrenia, having more Neanderthal admixture predicted less severe positive symptoms (p = .046). Finally, using 18 F-fluorodopa PET scanning in 172 healthy individuals, having greater Neanderthal introgression was significantly associated with lower dopamine synthesis capacity in the striatum and pons (p's < 2 Â 10 À5 ), which is fundamentally important in the pathophysiology and treatment of psychosis. These results may help to elucidate the evolutionary history of a devastating neuropsychiatric disease by supporting the notion of schizophrenia as a human-specific condition. Additionally, the relationship between Neanderthal admixture and dopamine function suggests a potential mechanism whereby Neanderthal admixture may have affected our gene pool to alter schizophrenia risk and/or course.

Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes

“…For example, Neandertal variants could persist in modern humans due to their neutral or even potentially advantageous effects at some point during recent evolution. Some previous studies have suggested that evolutionary forces such as positive selection [ 41 ] and Neandertal admixture [ 42 , 43 ] may be linked to mental disorders such as Schizophrenia. A more recent study subsequently demonstrated that when accounting for purifying selection there is no evidence for a significant Neandertal contribution [ 44 ].…”

Geneticist who unmasked lives of ancient humans wins medicine Nobel

“…Pääbo's work teasing out DNA from Neanderthals, Denisovans and other hominins also has important implications for modern medicine. Although the share of the human genome comprised of archaic DNA is small, this material seems to punch above its weight, making an important contribution to the risks of diseases ranging from schizophrenia 4 to severe . And people living on the Tibetan Plateau can thank Denisovans for gene variants linked to high-altitude adaptation 6 .…”

An indel introduced by Neanderthal introgression, rs3835124:ATTTATT > ATT, might contribute to prostate cancer risk by regulating PDK1 expression

“…As a result, current modern human genome contains a small amount (∼2%) of segments derived from Neanderthal introgression (Green et al., 2010; Sankararaman et al., 2014). Moreover, this DNA fraction has been proposed to be associated with multiple human phenotypes or diseases (Dannemann & Kelso, 2017; Dolgova & Lao, 2018; McArthur et al., 2021; Sankararaman et al., 2014; Simonti et al., 2016), including lipid catabolism (Khrameeva et al., 2014), skin pigmentation (Ding, Hu, Xu, Wang, Li et al., 2014; Hu et al., 2015; Vernot & Akey, 2014), type 2 diabetes (Williams et al., 2014), schizophrenia (Gregory et al., 2021), pain sensitivity (Zeberg et al., 2020), vitamin B1 metabolism (Ma & Xu, 2022), and environmental (Findley et al., 2021) or immune response (Abi‐Rached et al., 2011; Dannemann et al., 2016; Mendez et al., 2012; Quach et al., 2016; Temme et al., 2014), especially COVID‐19 susceptibility (Zeberg & Pääbo, 2020, 2021; Zhou et al., 2021). However, the contribution of Neanderthal introgression to cancer, a leading cause of death in contemporary human populations, has been hardly reported.…”