Family Size

Family size refers to the total number of children born to a woman or parent, or the total number of individuals within a household. It is a fundamental demographic characteristic that profoundly influences population dynamics, societal structure, and individual life trajectories. Understanding the factors that determine family size is crucial for demography, public health, and evolutionary biology.

Biological Basis

The capacity for human reproduction, and thus family size, has a significant biological basis, including underlying genetic factors. Studies on populations like the Hutterites, known for their large family sizes and birth rates, offer unique insights into the genetics of human reproductive potential. Research has utilized genome-wide association studies (GWAS) to identify candidate genetic variants, or single nucleotide polymorphisms (SNPs), associated with traits such as family size and birth rate. ^[1] These genetic investigations aim to uncover the biological mechanisms that contribute to variation in reproductive outcomes. For instance, initial GWAS in Hutterite men identified multiple loci associated with family size, with some of these findings further explored in validation studies. ^[1]

Clinical Relevance

Variations in family size are directly linked to human fertility, a trait of considerable clinical relevance. Genetic factors influencing family size can overlap with those affecting male and female fertility. Identifying genetic variants associated with family size can contribute to a deeper understanding of reproductive health, potentially informing clinical assessments and interventions for infertility or subfertility. The study of candidate genes for male fertility traits, for example, is inherently tied to the biological determinants of family size. ^[1]

Family size carries substantial social importance, impacting everything from resource allocation and economic planning to cultural norms and intergenerational relationships. Population studies that consider family size are essential for forecasting demographic trends, understanding societal aging, and planning for future educational, healthcare, and infrastructure needs. Furthermore, the study of family size in specific populations, such as the Hutterites, can provide valuable models for understanding human reproductive patterns in environments where social and cultural factors may allow for the expression of "true human reproductive potential," free from some of the external constraints seen in other societies. ^[1]

Methodological and Statistical Considerations

The initial genome-wide association study (GWAS) for family size was conducted within a relatively small Hutterite cohort, consisting of only 269 married men with proven fertility. ^[1] This restricted sample size inherently limited the statistical power to reliably detect genetic variants with subtle effects, a common challenge in GWAS that typically necessitates much larger cohorts to achieve robust genome-wide significance. ^[1] As a result, no associations in this discovery phase reached the stringent genome-wide significance threshold (approximately p < 10^-7), compelling the researchers to employ a more liberal p-value threshold (p < 10^-4) to identify candidate SNPs for subsequent validation. ^[1]

The reliance on a less stringent significance threshold in the initial discovery phase introduces a potential for an increased rate of false positive associations, as such a threshold would statistically predict approximately 25 findings by chance alone. ^[1] This approach also carries the risk of overestimating the effect sizes of truly associated variants. While a two-stage replication strategy involving an ethnically diverse cohort was implemented to address these limitations, the ultimate strength and consistent replication of all identified associations across independent populations are crucial for confirming their validity and generalizability. ^[1] For instance, one exonic SNP, rs3739474, despite validation, demonstrated a weaker association with family size than other nearby SNPs, illustrating the complexity in definitively pinpointing causal variants and the ongoing need for rigorous replication efforts. ^[1]

Population Specificity and Generalizability

The study's focus on the Hutterite population presents both unique advantages and inherent limitations regarding generalizability. The Hutterites are considered an excellent population for studying the genetics of fertility because their large family sizes and birth rates are believed to approximate the true human reproductive potential, minimizing confounding from modern reproductive choices. ^[1] However, this population's relatively isolated and genetically homogeneous nature means that genetic associations identified may not be directly transferable or hold the same significance in broader, more ethnically diverse human populations where genetic backgrounds, environmental influences, and reproductive behaviors vary considerably. ^[1] Although validation efforts were conducted in an ethnically diverse Chicago cohort, the extent to which the specific genetic architecture of fertility traits discovered in the Hutterites fully translates to other ancestral groups remains a critical consideration for broader interpretation. ^[1]

Environmental Context and Unidentified Genetic Factors

The unique environmental context of the Hutterite population, where family sizes are thought to reflect natural reproductive potential, inherently controls for some environmental confounders related to modern family planning practices. ^[1] However, this specificity also implies that the study's findings may not fully capture the influence of gene-environment interactions or other environmental factors that significantly modulate family size in more varied populations, such as socioeconomic factors, cultural norms, or access to reproductive healthcare. The absence of associations reaching genome-wide significance further indicates that many genetic variants contributing to family size likely possess individually small effects or participate in complex epistatic interactions that were not detectable with the current study's power. ^[1] This points to the presence of substantial 'missing heritability' for family size, suggesting that a comprehensive understanding will require larger, more diverse genetic studies that can simultaneously account for both genetic and environmental heterogeneity.

Variants

Genetic variations can profoundly influence an individual's biology, impacting traits that range from metabolic health to reproductive success and, consequently, family size. Among these, single nucleotide polymorphisms (SNPs) in genes like RPSAP53 and PCSK5 are of particular interest. The variant rs2991396 is located within RPSAP53, a pseudogene of ribosomal protein S3. While not directly coding for a protein, pseudogenes and long non-coding RNAs (like LINC00364, which RPSAP53 is sometimes associated with) can play critical regulatory roles, influencing the expression and stability of their protein-coding counterparts or other genes through mechanisms like competing endogenous RNA activity. Alterations here could subtly shift cellular processes, potentially affecting aspects of metabolic regulation or cell growth that are foundational to reproductive health. ^[2] Such genetic influences are often explored in large-scale studies that meticulously adjust for potential confounding factors like sex, oral contraceptive use, and body mass index to isolate the specific genetic effects on complex traits. ^[2]

Another significant variant, rs11144790, is found in the PCSK5 gene, which encodes Proprotein Convertase Subtilisin/Kexin Type 5. PCSK5 is a protease enzyme responsible for cleaving and activating a diverse array of precursor proteins, including hormones, growth factors, and adhesion molecules, essential for various physiological functions. Its involvement spans embryonic development, cell differentiation, and metabolic regulation, particularly in lipid metabolism. A variation like rs11144790 could alter the enzyme's efficiency, substrate specificity, or expression levels, leading to downstream effects on the activation of crucial proteins. These changes might impact metabolic balance or hormonal signaling pathways critical for fertility and successful pregnancies, thereby indirectly influencing the number of offspring an individual might have. Understanding these complex interactions requires careful consideration of various demographic and physiological covariates, such as gestational age and early growth patterns, in genetic analyses. ^[2]

Further genetic insights come from variants such as rs10966811 in RN7SKP120 (also associated with TUSC1) and rs2423942 in MACROD2. The TUSC1 (Tumor Suppressor Candidate 1) gene is recognized for its role in cell growth and differentiation, often implicated in pathways that regulate cell cycle progression and apoptosis. A variant like rs10966811 could affect the gene's expression or the stability of its product, potentially influencing cellular integrity and function. Similarly, MACROD2 (MACRO Domain Containing 2) encodes a protein integral to ADP-ribosylation signaling, a post-translational modification vital for DNA repair, chromatin remodeling, and the precise regulation of gene expression. The rs2423942 variant could impact the protein's ability to bind ADP-ribose or its overall function, thereby affecting genomic stability and cellular repair mechanisms. Both genes, through their fundamental roles in cell health and genomic integrity, can indirectly bear on reproductive fitness and the overall capacity for family formation, as disruptions could affect gamete quality, embryonic viability, or susceptibility to reproductive disorders. ^[2] Rigorous genome-wide association studies evaluating such loci often employ statistical methods, like the PLINK 'gxe' procedure, to compare effect sizes across different groups and identify significant gene-environment interactions. ^[2]

Key Variants

RS ID	Gene	Related Traits
rs2991396	RPSAP53 - LINC00364	family size
rs11144790	PCSK5	family size
rs10966811	RN7SKP120 - TUSC1	family size
rs2423942	MACROD2	family size

Defining Family Size and its Significance

Family size, in a genetic context, is precisely defined as a quantifiable trait reflecting human reproductive potential. Studies utilize family size as a direct or proxy measure to understand the underlying genetic architecture of fertility. In specific populations, such as the Hutterites, observed family sizes are considered to closely approximate the true biological limits of human reproduction. This trait is therefore central to research investigating the genetic factors influencing human reproductive capacity. ^[1]

Measurement Approaches and Research Criteria

The measurement of family size in genetic research typically involves its quantification as a phenotypic trait for genome-wide association studies (GWAS). In such analyses, family size is treated as a continuous or countable variable to identify genetic variants influencing its variation. Research criteria for identifying significant genetic associations with family size have included a liberal p-value threshold, such as p < 10^-4, in initial discovery stages. Such thresholds are employed to identify candidate single nucleotide polymorphisms (SNPs) for further validation in independent cohorts. ^[1]

Key terminology surrounding family size includes "birth rate" and broader concepts like "fertility" and "reproductive potential." "Family size" and "birth rate" are highly correlated phenotypes, both serving as indicators of an individual's reproductive output. These terms are integral to studies aiming to uncover the genetic underpinnings of human reproductive success. While specific categorical or dimensional classification systems for family size itself are not detailed, its quantitative nature allows for robust statistical analysis in genetic association studies. ^[1]

Genetic Architecture of Family Size

Family size, reflecting human reproductive potential, is significantly influenced by a complex interplay of genetic factors. Genome-wide association studies (GWAS) have identified numerous inherited genetic variants, specifically single nucleotide polymorphisms (SNPs), associated with family size. For instance, research in populations like the Hutterites, known for approximating true human reproductive potential, revealed 61 SNPs significantly associated with family size, located across 28 independent genomic regions. ^[1] These findings suggest that variations in specific genetic loci contribute to the overall determination of an individual's reproductive capacity, impacting the number of offspring. Furthermore, complex traits like family size can be influenced by gene-gene interactions, where the effect of one gene is modified by another, a phenomenon observed, for example, in studies on litter size in mice. ^[3]

Polygenic Influence and Regulatory Mechanisms

The genetic basis of family size is characterized by a polygenic architecture, meaning it is shaped by the combined contributions of multiple independent genetic loci rather than a single gene. Studies have shown that reproductive phenotypes, including family size, decrease with an increasing number of risk genotypes or alleles, reinforcing the concept of many genetic variants cumulatively influencing the trait. ^[1] Beyond direct coding variations, the effects of genetic variation can be regulatory in nature, influencing gene expression without altering the protein sequence itself. For example, some identified SNPs associated with family size have been predicted to function as expression quantitative trait loci (eQTLs), affecting the expression levels of nearby genes and thereby modulating biological pathways relevant to fertility. ^[1] This intricate regulatory control highlights how genetic predispositions can subtly, yet significantly, impact an individual's reproductive outcomes.

Genetic Architecture of Human Reproductive Potential

Family size, a complex human trait reflecting reproductive potential, is influenced by a combination of genetic and environmental factors. Studies in populations like the Hutterites, who traditionally desire large families and minimize non-genetic influences on reproductive practices, provide a unique opportunity to uncover the genetic underpinnings of natural human fertility. This population exhibits a high median sibship size and a low interbirth interval, making them an ideal model for genetic studies of fertility. Importantly, family size and birth rate are highly heritable traits within this population, with broad heritability estimated at 0.72 for family size and 0.65 for birth rate, indicating a substantial genetic component. ^[1]

Genome-wide association studies (GWAS) have been instrumental in identifying specific genetic regions associated with family size. For instance, initial GWAS in Hutterites identified 61 single nucleotide polymorphisms (SNPs) associated with family size at 28 independent genomic loci. These findings highlight that variation in human reproductive capacity is not controlled by a single gene but rather by multiple genetic elements scattered across the genome. While these studies have successfully pointed to genomic regions, the precise genes and their functional roles often require further detailed investigation beyond the initial association. ^[1]

Molecular Clues from Candidate Genes and Loci

Many of the SNPs associated with family size are located within or in close vicinity to known genes, suggesting that these genes may play a direct or regulatory role in human fertility. Specifically, 43 of the identified SNPs were found within coding regions or within 100 kilobases of 23 different genes across 22 loci. Although the exact molecular and cellular pathways influenced by these specific SNPs are still being elucidated, their proximity to genes implies potential effects on gene function, expression patterns, or regulatory networks critical for reproductive processes. The validation of these genetic associations often involves examining their impact on more direct fertility measures, such as sperm parameters. ^[1]

Further insights into the molecular basis of reproductive traits come from quantitative trait locus (QTL) mapping studies in animal models, such as mice and pigs, which have identified regions influencing litter size, sperm quality, and ovulation rates. These studies, while often identifying broad genomic regions, underscore the involvement of various genes and pathways in mammalian reproduction. The challenge lies in translating these broad associations into specific molecular mechanisms, such as identifying critical proteins, enzymes, or hormones whose functions are modulated by these genetic variants. Understanding these molecular underpinnings is crucial for a comprehensive biological explanation of how genetic variations contribute to the observed differences in family size. ^[4]

Physiological Determinants of Fertility

The genetic factors influencing family size often converge on key physiological processes essential for successful reproduction. Although the provided context does not detail specific molecular pathways for the identified SNPs, the validation studies linking these SNPs to "male fertility traits" and "sperm parameters" in ethnically diverse men from Chicago suggest an impact on the male reproductive system. These parameters, which include aspects of sperm quality and function, are crucial for fertilization and thus directly contribute to an individual's reproductive success and, consequently, family size. ^[1]

The overall process of reproduction involves intricate tissue and organ-level interactions, from gamete production in the gonads to successful fertilization and embryonic development. Disruptions in any of these homeostatic processes, whether due to genetic predispositions or external factors, can lead to reduced fertility. For example, genetic variants might affect the development or function of reproductive organs, the synthesis or reception of critical hormones, or the cellular functions within germ cells. While specific pathophysiological processes linked to family size SNPs are not fully detailed, the identification of genetic loci suggests that variations in these fundamental biological processes collectively contribute to the observable range of family sizes in human populations. ^[5]

Interplay of Genetics and Environment in Reproduction

While genetic factors contribute significantly to family size, environmental and socio-cultural influences also play a profound role in shaping reproductive outcomes. Factors such as socioeconomic status, education level, cultural beliefs, and religious dictates can substantially impact reproductive behavior and family planning decisions. This complex interplay often makes it challenging to isolate purely genetic effects in human fertility studies. ^[1]

For instance, the concept of "cultural inheritance" has been proposed to explain correlations in family sizes across generations, highlighting the transmission of reproductive behaviors independent of genetic mechanisms. By studying populations like the Hutterites, where non-genetic factors are largely minimized due to their communal lifestyle and religious adherence, researchers can better delineate the genetic contributions to natural variation in fertility. Understanding this intricate interaction between inherited genetic predispositions and external environmental factors is essential for a holistic view of the biological background of family size. ^[6]

Cohort Studies and Genetic Influences on Family Size

Population studies leveraging specific cohorts have been instrumental in exploring the genetic underpinnings of family size, a key indicator of human reproductive potential. One notable study conducted a genome-wide association study (GWAS) in the Hutterite population, identifying 61 single nucleotide polymorphisms (SNPs) associated with family size at a significance threshold of p < 10^-4, located at 28 independent loci. Forty-three of these SNPs were found within or near 23 distinct genes across 22 loci, suggesting specific genetic regions influencing reproductive output. The Hutterites were chosen for this research due to their large family sizes and birth rates, which are considered to closely reflect natural human reproductive potential, offering a unique opportunity to study genetic factors in a relatively isolated population. ^[1]

While the Hutterite study provided valuable insights into genetic determinants within a specific group, the utility of large-scale biobanks and diverse cohorts for comprehensive population studies is also evident. Biobanks such as the UK Biobank, with its extensive genetic and health data from approximately 500,000 participants, represent a powerful resource for investigating complex traits and disease associations, including those related to reproductive health or family history of disease, by allowing researchers to explore broad demographic factors and genetic variations across a large and representative population. ^[7] Such large cohorts enable the identification of temporal patterns and longitudinal findings that might not be discernible in smaller, more homogenous populations, thereby enhancing the generalizability of findings regarding complex traits influenced by both genetic and environmental factors.

Cross-Population Genetic Investigations of Reproductive Traits

Investigating family size across different populations is crucial for understanding the interplay of ancestry, geographic variations, and population-specific genetic effects on reproductive traits. The initial GWAS for family size in the Hutterites, while powerful due to the population's unique demographic characteristics, had a relatively small sample size for a genome-wide study, consisting of 269 married men with proven fertility. ^[1] To address this limitation and enhance the generalizability of their findings, the researchers employed a two-stage strategy. This involved identifying candidate SNPs in the Hutterite discovery cohort and subsequently conducting validation studies in ethnically diverse men from the Chicago area. ^[1]

This cross-population approach is vital for discerning whether genetic associations observed in one population are universal or population-specific. Differences in genetic backgrounds, linkage disequilibrium patterns, and environmental exposures across diverse ethnic groups can lead to variations in genetic effect sizes or even the identification of entirely different genetic loci. The validation in an ethnically diverse cohort helps confirm the robustness of initial findings and provides insights into the broader applicability of identified genetic variants, moving beyond the specific context of the Hutterites to more general human populations. ^[1]

Epidemiological Associations and Methodological Considerations

Epidemiological studies of family size often consider its associations with various demographic and socioeconomic factors, alongside genetic influences. The Kosova et al. study, for instance, investigated not only family size but also birth rate, noting their high correlation, which highlights the interconnectedness of these reproductive endpoints. ^[1] Methodologically, GWAS for quantitative traits like family size typically involve statistical adjustments for covariates such as age, gender, and sometimes height or body mass index, using linear regression or linear mixed models to account for potential confounding factors. ^[8]

A critical aspect of population genetic studies involves rigorous methodological considerations to ensure the validity and generalizability of findings. Study designs frequently employ imputation to infer ungenotyped variants, requiring high imputation quality scores (e.g., INFO score > 0.7) and careful filtering of variants based on minor allele count and Hardy-Weinberg equilibrium to maintain data quality. ^[9] Furthermore, accounting for population stratification and cryptic relatedness is essential to prevent spurious associations. Techniques such as principal component analysis (PCA) are commonly used to correct for population structure, while methods like LD score regression can address inflation in test statistics due to relatedness. ^[8] The representativeness and sample size of cohorts are crucial; for example, while the Hutterite population is genetically informative, its relatively small size necessitated a two-stage validation strategy in a larger, more diverse population to enhance the generalizability of the findings on family size. ^[1]

Ethical Dimensions of Genetic Insights into Family Size

The identification of genetic variants associated with traits like family size raises significant ethical questions regarding their application and interpretation. As research identifies candidate single nucleotide polymorphisms (SNPs) for family size and birth rate ^[1] the ethical debates surrounding genetic testing for such complex traits become paramount. Informed consent is crucial, ensuring individuals understand the implications of learning about their genetic predispositions for fertility, which may impact deeply personal reproductive choices. There are concerns about how this knowledge might influence societal expectations or individual decisions about having children, potentially creating pressure or altering perceptions of reproductive potential.

Furthermore, these genetic insights raise serious privacy concerns and the specter of genetic discrimination. If genetic markers for family size are identified ^[1] robust data protection measures are essential to safeguard this sensitive information. Without stringent regulations, there is a risk that individuals could face discrimination in areas such as employment, insurance, or even social standing based on their perceived genetic capacity for reproduction. The delicate balance between scientific advancement and the protection of individual rights and autonomy must be carefully navigated to prevent misuse of genetic data related to fertility.

Sociocultural Context and Implications for Equity

Genetic research into family size is deeply intertwined with sociocultural factors, which must be considered to prevent unintended social implications. Studies acknowledge that "nongenetic factors, such as socioeconomic status, education level, cultural beliefs, and religious dictates, influence human reproductive behavior". ^[1] For instance, populations like the Hutterites "uniformly desire large families" due to their communal lifestyle and religious doctrine. ^[1] Insights into the genetics of family size, therefore, could interact with these deeply ingrained cultural norms, potentially leading to stigma for individuals whose genetic profiles might be perceived as deviating from cultural expectations for fertility or family size.

Addressing health equity and preventing disparities is also critical when exploring genetic contributions to family size. Research involving diverse populations, such as "ethnically diverse men from the Chicago area" in addition to a founder population ^[1] underscores the need for equitable application of findings. It is imperative to ensure that any potential fertility-related interventions or counseling derived from such genetic insights are accessible to all, regardless of socioeconomic status or geographic location, to avoid exacerbating existing health disparities and ensuring fair resource allocation.

Policy, Regulation, and Responsible Research Practices

The advancement of genetic studies on family size necessitates robust policy and regulatory frameworks to ensure ethical conduct and data governance. Research practices emphasize the importance of "written informed consent" and adherence to "human subjects protections" in accordance with guidelines such as the Declaration of Helsinki. ^[10] These principles must guide the development of genetic testing regulations and clinical guidelines specifically tailored for fertility-related genetic information, addressing how results are communicated, interpreted, and utilized in clinical settings. Data protection is paramount, especially when dealing with personal and potentially sensitive genetic information that could be stored in biobanks. ^[10]

Responsible research ethics are particularly crucial when studying vulnerable populations or founder populations, such as the Hutterites, who are noted for their "high participation" and "ideal" characteristics for genetic studies due to minimized nongenetic factors. ^[1] Policies must ensure that the interests and autonomy of these communities are always protected, preventing exploitation and ensuring that research benefits are equitably shared. Furthermore, from a global health perspective, the implications of genetic insights into family size demand thoughtful consideration of resource allocation and the potential for these advancements to disproportionately impact different regions or populations, highlighting the need for ethical oversight that transcends national boundaries.

Frequently Asked Questions About Family Size

These questions address the most important and specific aspects of family size based on current genetic research.

1. Why do some couples have huge families so easily?

It's true that some individuals and populations seem to have many children with greater ease, and genetics play a significant role. Studies in populations like the Hutterites, known for their large families, show that certain genetic factors contribute to higher reproductive potential. These biological underpinnings can make it naturally easier for some to achieve larger family sizes.

2. Will my family's history affect my family size?

Yes, your family's history of having many children can indicate a genetic predisposition. Family size has a biological basis, and these genetic factors can be passed down. While personal choices and environment also matter, your inherited traits can influence your reproductive capacity.

3. Could my background affect how many children I might have?

Your ethnic background can indeed play a role. Genetic variations associated with family size and fertility can differ across populations. While studies identify general genetic factors, it's important to remember that findings from one specific group may not fully apply to all diverse ancestral groups.

4. Is having a big family mostly about personal choices?

While personal choices are certainly a major factor in modern societies, genetics also contribute significantly to the capacity for having a large family. There's a biological basis to human reproductive potential, meaning some individuals naturally have a higher inherent ability to reproduce, independent of their conscious family planning decisions.

5. Why do some friends seem to get pregnant so much faster than me?

Individual differences in fertility are common, and genetics are a key part of this. Genetic factors that influence overall family size can overlap with those affecting how easily someone conceives, for both men and women. These underlying biological differences can make conception quicker for some individuals.

6. Could a DNA test help me understand my chances of having kids?

A DNA test could potentially offer some insights into your reproductive health and capacity. By identifying genetic variants associated with family size and fertility, such tests can contribute to a deeper understanding of your biological potential. However, these tests are still evolving and should be interpreted by a healthcare professional.

7. Do my genes play a role in how many children I can have?

Absolutely, your genes do play a role in your reproductive potential and, consequently, the number of children you might have. Research has identified specific genetic variants associated with traits like family size and birth rate. These genetic factors form a significant part of the biological basis for human reproduction.

8. Are there health reasons why some struggle to have kids?

Yes, there are often biological and health reasons why some individuals or couples struggle to have children. Genetic factors influencing family size are directly linked to human fertility. Identifying specific genetic variants can help explain issues like infertility or subfertility, informing potential clinical assessments and interventions.

9. Why do some societies have many more children than others?

Differences in family size across societies are complex, influenced by social, cultural, and economic factors, but underlying genetic potential also plays a part. In some populations, where modern reproductive choices are less prevalent, the "true human reproductive potential" might be more evident, revealing natural biological variations in fertility rates.

10. If I want a big family, can I overcome any genetic hurdles?

While your genetic makeup certainly influences your reproductive potential, it's not the sole determinant. Environmental factors, lifestyle choices, and access to healthcare can significantly modulate family size. While genetics set a biological foundation, a comprehensive approach considering both genetic predispositions and environmental support is crucial.

This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Kosova, G. "Genome-wide association study identifies candidate genes for male fertility traits in humans." American Journal of Human Genetics, vol. 90, no. 6, 8 June 2012, pp. 950–961.

[2] Sabatti C, et al. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet. 2009.

[3] Rocha, J.L., et al. "A large-sample QTL study in mice: III. Reproduc-tion." Mamm. Genome, vol. 15, 2004, pp. 878–886.

[4] Allan, M.F., et al. "Conﬁrmation of quantitative trait loci using a low-density single nucleotide polymorphism map for twinning and ovulation rate on bovine chromosome 5." J. Anim. Sci., vol. 87, 2009, pp. 46–56.

[5] Cooke, H.J., and Saunders, P.T. "Mouse models of male infertility." Nat. Rev. Genet., vol. 3, 2002, pp. 790–801.

[6] Austerlitz, F., and Heyer, E. "Social transmission of reproductive behavior increases frequency of inherited disorders in a young-expanding population." Proc. Natl. Acad. Sci. USA, vol. 95, 1998, pp. 15140–15144.

[7] Sun, B. B., et al. "Genomic atlas of the human plasma proteome." Nature, vol. 558, no. 7708, 2018, pp. 73–79.

[8] Styrkarsdottir, U., et al. "GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures." Nature Communications, vol. 10, no. 1, 2019, 2049.

[9] Marioni, R. E., et al. "GWAS on family history of Alzheimer's disease." Translational Psychiatry, vol. 7, no. 5, 2017, e1129.

[10] Bray, M. J., et al. "Transethnic and race-stratified genome-wide association study of fibroid characteristics in African American and European American women." Fertility and Sterility, vol. 112, no. 3, 1 Sept. 2019, pp. 529–541.e2.