Heritability

Genetic heritability is a metric of the amount of phenotypic variation in a given trait explained by genetics, the remaining amount being attributed to environmental factors¹. Due to the complex interplay between genetics and environmental factors a number of these environmental elements are inheritable too, though not necessarily directly influenced by genetics^2,3. Some of these factors that display a degree of non-genetic inheritability include SES⁴, exposure to environmental toxins⁵, educational attainment², and other factors related to wealth and geography^6,7. These factors can perhaps be considered “classic heritability”, the degree of variance explained by the combined effects of factors inherited from ones ancestors. However, when referring to “heritability” in this thesis it refers to genetic heritability unless otherwise specified.

Heritability provides a metric by which researchers can quantify the biological relevance of the genome in human traits and disease. Due to the nearly infinite number of environmental factors at play, identifying traits with a high degree of genetic heritability can instead more readily provide an avenue for investigation of the biological pathways associated with the traits by analyzing the SNPs driving the heritability⁹. In this case, a high degree of heritability would provide researchers with confidence that the genome plays a big role in the trait of interest, and thus makes genetic analysis a worthwhile effort⁹. That being said, a low heritability does not mean that genetic analysis is not valuable, since it is still possible to derive meaningful biological insights into the trait, with the caveat that these findings amount to a lower percentage of phenotypic variance in the trait of interest⁹.

Within genetic heritability, there are two main approaches for calculating heritability: twin-based and SNP-based heritability (h²_SNP). The former is based on twin studies, and the latter is based on the additive effects of SNPs^10,11. Heritability estimates from twin-based studies are usually considerably higher than those from SNP-based studies¹⁰. Twin-based estimates are usually based on the differences in phenotype between both halves of monozygotic and dizygotic twins¹². SNP-based heritability is commonly defined as a measure of the proportion of phenotypic variance explained by additive effects of all SNP in the genome and is usually calculated using summary statistics from a GWAS¹³. The difference between the twin-based and the SNP-based heritability estimates is also referred to as the “missing heritability problem”¹⁴. A major reason this gap exists is due to the way heritability estimates are calculated¹⁵. Whereas twin-based studies use a more direct approach by targeting individuals with known shared DNA, the SNP-based estimates rely on GWAS summary statistics that require sufficient power to detect the variants involved^10,15,16. It is therefore reasonable to expect that with increased GWAS statistical power the “missing heritability gap” is likely to shrink, within certain boundaries^10,15.

Due to the definition of heritability (i.e. the proportion of variance in a trait explained by genetics), the value to denote heritability has to lie between 0 and 1. For a trait that is entirely modified by genetics and not influenced by environment or gene-by-environment interactions (e.g. Huntington’s diease) the heritability would be close to 1, or 100%. Most traits however are the result of a complex interaction between genetics, gene-by-environment interactions, and environmental factors¹⁷. For example, it is clear that for most healthy individuals one’s height is strongly influenced by the height of their parents. However, alterations in diet, disease, and exposure to environmental toxins can influence how tall someone will grow^14,18. These factors are not immediately obvious in more complex traits such as depression and many other psychiatric disorders. Heritability estimates for schizophrenia based on twin-studies lie consistently around 80%^19,20, whereas estimates of SNP-based heritability for schizophrenia is approximately 23% at the moment²¹. Similar gaps exist for BIP (h²_twin = 75%, h²_SNP = 25%), ASD (h²_twin = 80%, h²_SNP = 17%), ADHD (h²_twin = 75%, h²_SNP = 28%), and MDD (h²_twin = 37%, h²_SNP = 21%)^21,22.

1.

Speed D, Cai N, Johnson MR, Nejentsev S, Balding DJ, the UCLEB Consortium. Reevaluation of SNP heritability in complex human traits. Nature Genetics [Internet]. 2017 Jul 1;49(7):986–92. Available from: https://doi.org/10.1038/ng.3865

2.

Branigan AR, McCallum KJ, Freese J. Variation in the Heritability of Educational Attainment: An International Meta-Analysis. Social Forces [Internet]. 2013 Sep 1 [cited 2022 May 29];92(1):109–40. Available from: https://doi.org/10.1093/sf/sot076

3.

Tenesa A, Haley CS. The heritability of human disease: Estimation, uses and abuses. Nature Reviews Genetics [Internet]. 2013 Feb 1;14(2):139–49. Available from: https://doi.org/10.1038/nrg3377

4.

Clark G, Cummins N. Surnames and Social Mobility in England, 1170–2012. Human Nature [Internet]. 2014 Dec 1;25(4):517–37. Available from: https://doi.org/10.1007/s12110-014-9219-y

5.

Blake GE, Watson ED. Unravelling the complex mechanisms of transgenerational epigenetic inheritance. Current Opinion in Chemical Biology [Internet]. 2016 Aug 1;33:101–7. Available from: https://www.sciencedirect.com/science/article/pii/S1367593116300849

6.

Grossniklaus U, Kelly WG, Ferguson-Smith AC, Pembrey M, Lindquist S. Transgenerational epigenetic inheritance: How important is it? Nature Reviews Genetics [Internet]. 2013 Mar 1;14(3):228–35. Available from: https://doi.org/10.1038/nrg3435

7.

Schiller JS, Lucas JW, Peregoy JA. Summary health statistics for u.s. Adults: National health interview survey, 2011. Vital Health Stat 10. 2012 Dec;(256):1–218.

8.

Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh PR, et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nature Genetics [Internet]. 2015 Nov 1;47(11):1228–35. Available from: https://doi.org/10.1038/ng.3404

9.

Visscher PM, Hill WG, Wray NR. Heritability in the genomics era — concepts and misconceptions. Nature Reviews Genetics [Internet]. 2008 Apr 1;9(4):255–66. Available from: https://doi.org/10.1038/nrg2322

10.

Nolte IM, van der Most PJ, Alizadeh BZ, de Bakker PI, Boezen HM, Bruinenberg M, et al. Missing heritability: Is the gap closing? An analysis of 32 complex traits in the Lifelines Cohort Study. European Journal of Human Genetics [Internet]. 2017 Jul 1;25(7):877–85. Available from: https://doi.org/10.1038/ejhg.2017.50

11.

Polderman TJC, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nature Genetics [Internet]. 2015 Jul 1;47(7):702–9. Available from: https://doi.org/10.1038/ng.3285

12.

Wray NR, Visscher P. Estimating trait heritability. Nature Education. 2008;1(1):29.

13.

Yang J, Zeng J, Goddard ME, Wray NR, Visscher PM. Concepts, estimation and interpretation of SNP-based heritability. Nature Genetics [Internet]. 2017 Sep 1;49(9):1304–10. Available from: https://doi.org/10.1038/ng.3941

14.

Maher B. Personal genomes: The case of the missing heritability. Nature [Internet]. 2008 Nov 1;456(7218):18–21. Available from: https://doi.org/10.1038/456018a

15.

Young AI. Solving the missing heritability problem. PLoS Genet [Internet]. 2019 Jun 24;15(6):e1008222–2. Available from: https://pubmed.ncbi.nlm.nih.gov/31233496

16.

Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature [Internet]. 2009 Oct 8;461(7265):747–53. Available from: https://pubmed.ncbi.nlm.nih.gov/19812666

17.

Wainschtein P, Jain D, Zheng Z, Aslibekyan S, Becker D, Bi W, et al. Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. Nature Genetics [Internet]. 2022 Mar 1;54(3):263–73. Available from: https://doi.org/10.1038/s41588-021-00997-7

18.

Jelenkovic A, Sund R, Hur YM, Yokoyama Y, Hjelmborg JvB, Möller S, et al. Genetic and environmental influences on height from infancy to early adulthood: An individual-based pooled analysis of 45 twin cohorts. Scientific Reports [Internet]. 2016 Jun 23;6(1):28496. Available from: https://doi.org/10.1038/srep28496

19.

Hilker R, Helenius D, Fagerlund B, Skytthe A, Christensen K, Werge TM, et al. Heritability of Schizophrenia and Schizophrenia Spectrum Based on the Nationwide Danish Twin Register. Biol Psychiatry. 2018 Mar 15;83(6):492–8.

20.

Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: Evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003 Dec;60(12):1187–92.

21.

Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics [Internet]. 2013 Sep 1;45(9):984–94. Available from: https://doi.org/10.1038/ng.2711

22.

Sullivan PF, Daly MJ, O’Donovan M. Genetic architectures of psychiatric disorders: The emerging picture and its implications. Nat Rev Genet. 2012 Jul 10;13(8):537–51.